Fused heteroaryl derivatives

ABSTRACT

The present invention provides a pharmaceutical composition which is useful as a phosphatidylinositol 3 kinase (PI3K) inhibitor and an antitumor agent, and it provides a novel bicyclic or tricyclic fused heteroaryl derivative or a salt thereof which possesses an excellent PI3K inhibiting activity and cancer cell growth inhibiting activity.

This application is a divisional of U.S. Ser. No. 09/843,615 filed Apr.26, 2001, and also claims priority under 35 U.S.C. §119(c) from U.S.Provisional Applications Nos. 60/200,537 filed Apr. 27, 2000 and60/200,481 filed Apr. 28, 2000.

FIELD OF THE INVENTION

The present invention relates to fused heteroaryl derivatives which areuseful as medicaments, more particularly as phosphatidylinositol3-kinase (PI3K) inhibitors and carcinostatic agents.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one ofphospholipids in cell membranes. In recent years it has become clearthat PI plays an important role also in intracellular signaltransduction. It is well recognized in the art that especially PI (4,5)bisphosphate (PI(4,5)P2) is degraded into diacylglycerol and inositol(1,4,5) triphosphate by phospholipase C to induce activation of proteinkinase C and intracellular calcium mobilization, respectively [M. J.Berridge et al., Nature, 312, 315 (1984); Y Nishizuka, Science, 225,1365 (1984)].

Turning back to the late 1980s, PI3K was found to be an enzyme tophosphorylate the 3-position of the inositol ring ofphosphatidylinositol [D. Whitman et al., Nature, 332, 664 (1988)].

PI3K was originally considered to be a single enzyme at the time whenPI3K was discovered. Recently it was clarified that a plurality ofsubtypes are present in the PI3K. Three major classes of PI3Ks have nowbeen identified on the basis of their in vitro substrate specificity [B.Vanhaesebroeck, Trend in Biol. Sci., 22, 267(1997)].

Substrates for class I PI3Ks are PI, PI(4)P and PI(4,5)P2. In thesesubstrates, PI(4,5)P2 is the most advantageous substrate in cells. ClassI PI3Ks are further divided into two groups, class Ia and class Ib, interms of their activation mechanism. Class Ia PI3Ks, which include PI3Kp110α, p110β and p110δ subtypes, are activated in the tyrosine kinasesystem. Class Ib PI3K is a p110γ subtype activated by a Gprotein-coupled receptor.

PI and PI(4)P are known as substrates for class II PI3Ks but PI(4,5)P2is not a substrate for the enzymes of this class. Class II PI3Ks includePI3K C2α, C2β and C2γ subtypes, which are characterized by containing C2domains at the C terminus, implying that their activity will beregulated by calcium ions. The substrate for class III PI3Ks is PI only.A mechanism for activation of the class III PI3Ks is not clarified yet.Since each subtype has its own mechanism for the regulating activity, itis considered that the respective subtypes will be activated dependingon their respective stimuli specific to each of them.

In the PI3K subtypes, the class Ia subtype has been most extensivelyinvestigated to date. The three subtypes of class Ia are hetero dimersof a catalytic 110 kDa subunit and regulatory subunits of 85 kDa and 55kDa. The regulatory subunits contain SH2 domains and bind to tyrosineresidues phosphorylated by growth factor receptors with a tyrosinekinase activity or oncogene products thereby inducing the PI3K activityof the p110 catalytic subunit. Thus, the class Ia subtypes areconsidered to be associated with cell proliferation and carcinogenesis.Furthermore, the class Ia PI3K subtypes bind to activated ras oncogeneto express their enzyme activity. It has been confirmed that theactivated ras oncogene is found to be present in many cancers,suggesting a role of class Ia PI3Ks in carcinogenesis.

As explained above, PI3K inhibitors are expected to be a novel type ofmedicaments useful against cell proliferation disorders, especially ascarcinostatic agents. As for the PI3K inhibitor, wortmannin [H. Yano etal., J. Biol. Chem., 263, 16178 (1993)] and LY294002 [J. Vlahos et al.,J. Biol. Chem., 269, 5241(1994)] which is represented by the formulabelow are known. However, development of PI3K inhibitors having a morepotent cancer cell growth inhibiting activity is desired.

Japanese Patent KOKAI (Laid-Open) No. 6-220059 discloses fusedheteroaryl derivatives shown by formula (a) below which possess anactivity of reducing the blood glucose level. Furthermore, compoundsshown by formula (b) and formula (c) below are described in Indian J.Chem., Sect. B (1993), 32B (9), 965-8 and J. Heterocycl. Chem. (1992),29 (7), 1693-702, respectively. In addition, Al-AzharBull. Sci. (1992),3(2), 767-75 discloses a compound shown by formula (d) below. However,none of these prior art publications disclose or suggest the PI3Kinhibiting activity.

In formula (a) above, Z is O, S or ═N—R0, R1 is an amino which may besubstituted, a heterocyclic group which may be substituted, etc.; R2 iscyano, an amino which may be substituted, or a heterocyclic group whichmay be substituted; and with respect to the remaining substituents, seethe specification of the patent. In formula (b) and (c) above, R is a(substituted) amino or a (substituted) nitrogen-containing saturatedheterocyclic group.

Publication No. WO98/23613 discloses fused pyrimidine derivatives, suchas 7H-pyrrolo[2,3-d]pyrimidine derivatives, which having a tyrosinekinase receptor inhibiting activity and which are useful ascarcinostatic agents, wherein the fused pyrimidine derivatives have atits fourth position a particular-heteroaryl-substituted amino,pheny-substituted amino, or indole-1-yl, and have no substituent at itssecond position.

Following compounds are known among the compounds shown by generalformula (I), whereas “A” ring is a ring shown by (b);

(1) Ann. Pharm. Fr. (1974), 32(11), 575-9 discloses4-(4-morpholinyl)-2-phenylpirido[2,3-d]pyrimidine as a compound havingantiinflammatory and spasmolytic activities,

(2) Chem. Pharm. Bull. (1976), 24(9), 2057-77 discloses4-(4-morpholinyl)-2-phenylpirido[2,3-d]pyrimidine-7(1H)-one as acompound having a diuretic activity,

(3) Khim.-Farm. Zh. (1993), 7(7), 16-19 and Khim. Geterotsiki. Soedin.(1971), 7(3), 418-20 disclose 4-(4-morpholinyl)-2-phenyl-6-quinazolinoland 6-methoxy-4-(4-morpholinyl)-2-phenylquinazoline as compounds havingan antibiotic activity,

(4) Publication No. WO2000/41697 discloses2,4-diamino-6-phenyl-8-piperidinopyrimido[5,4-d]pyrimidine as a compoundhaving celebral ischemia prevention and treatment effects,

(5) Publication No. WO99/32460 discloses, as cardiovascular drugs,compounds of general formula (Ib) described hereinafter wherein B is abenzene ring, W is N, n is 2 or 3, existing R1's are all —OMe, and R4bis an unsubstituted phenyl or a phenyl substituted by 1 to 3substituents which are selected from -a halogen, NO2, -a lower alkyl,—O-a lower alkyl, -a halogenated lower alkyl and —CONRaRc,

(6) Publication No. BE841669 discloses, as antiparasitics, compounds ofgeneral formula (Ib) described hereinafter wherein B is a benzene ring,W is N, n is 1, R1 is -a halogen or -a lower alkyl, and R4b is -(animidazolyl which may have one or more substituents),

(7) Publication No. WO99/43682 discloses, as antianxiety agents,compounds of general formula (Ib) described hereinafter wherein B is athiophene ring, and W is CH,

(8) Japanese Patents KOKAI (Laid-Open) Nos. 62-10085 and 61-158983disclose compounds of general formula (Ib) described hereinafter whereinB is an imidazole ring, and W is N, whereas the compounds have anantiinflammatory activity, a platelet aggregation inhibiting activity,etc.,

(9) U.S. Pat. No. 3,873,545 and Act Pol. Pharm. (1994), 51(4-5), 359-63disclose compounds of general formula (Ib) described hereinafter whereinB is a pyridine ring, and R4b is an unsubstituted phenyl, anunsubstituted pyridyl, or -a lower alkylene-(a nitrogen-containingsaturated heterocyclic group which may have one or more substituents),whereas the compounds have a spasmolytic, diuretic or hypotensiveactivity,

(10) U.S. Pat. No. 2,940,972 discloses compounds of general formula (Ib)described hereinafter wherein B is a pyrazine ring, and R4b is anunsubstituted phenyl, or a benzyl, whereas the compounds have a coronarydilating or sedative activity,

(11) U.S. Pat. No. 3,753,981 and Germnan Patent Publication No.2,140,280 disclose compounds of general formula (Ib) describedhereinafter wherein B is a benzene ring, and R4b is a styryl or2-(5-nitro-2-furyl)vinyl, whereas the compounds have an antiinflammatoryor antibiotic activity, and

(12) Eur. J. Med. Chem. (1996), 31(5), 417-425, discloses compounds ofgeneral formula (Ib) described hereinafter wherein B is a benzene ring,W is CH, and R2 and R3 are bonded together with an adjacent N atom toform -(piperidinyl which may have one or more substituents) or-(piperazinyl which may have one or more substituents), as compoundsworking as a benzodiazepine receptor ligand, U.S. Pat. No. 4,560,692discloses them as those having a spasmolytic and ataractic activity, andJapanese Patents KOKAI (Laid-Open) No. 2-129169 discloses them as thosehaving a lipoperoxidation inhibiting activity.

Furthermore, compounds of general formula (Ib) described hereinafterwherein B is a pyridine ring and n is 0 are disclosed in Japanese PatentKOKAI (Laid-Open) No. 51-138689 (antiparasitics), Japanese Patent KOKAI(Laid-Open) No. 56-120768 (a dye component for thermosensitive recordingmaterials), Antimicrob. Agents Chemother., (1975), 8 (2), 216-19 (anantibacterial activity), Cancer Res. (1975), 35 (12), 3611-17 (amutagenic activity), CA 64: 19608c, Collect. Czech. Chem. Commun.,(1994), 59 (6), 1463-6, U.S. Pat. No. 5,304,554 (an anti-HIV activity),Chem. Pharm. Bull., (1982), 30(6), 1974-9, and J. Heterocycl. Chem.(1980), 17(5), 1029-34. However, none of the prior publications teach oreven suggest the PI3K inhibiting activity and carcinostatic activity.

SUMMARY OF THE INVENTION

The present inventors have performed extensive investigations oncompounds with a PI3K inhibiting activity. As a result, it has beenfound that novel fused heteroaryl derivatives have an excellent PI3Kinhibiting activity as well as a cancer cell growth inhibiting activity.Based on the finding, it has been discovered that the fused heteroarylderivatives could be excellent PI3K inhibitors and antitumor agents. Thepresent invention has thus been achieved.

Therefore, the present invention relates to pharmaceutical compositions,which are PI3K inhibitors or antitumor agents, comprising a fusedheteroaryl derivative represented by general formula (I) below or a saltthereof and a pharmaceutically acceptable carrier.

wherein:

B represents a benzene ring, or a 5- or 6-membered monocyclic heteroarylcontaining 1 to 2 hetero atoms selected from O, S and N;

R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -acycloalkyl, -an aryl which may have one or more substituents, -aheteroaryl which may have one or more substituents, -a halogen, —NO2,—CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO— Rb, —COORb,—CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O— CO—NRaRbor —NRaCO—COORb, —CO-a nitrogen-containing saturated heterocyclic group,—CONRa-a lower alkylene-ORb, —CONRa-a lower alkylene-NRb, —O-a loweralkylene-ORb, —O-a lower alkylene-O-a lower alkylene-ORb, —O-a loweralkylene-NRaRb, —O-a lower alkylene-O-a lower alkylene-NRaRb, —O-a loweralkylene-NRc-a lower alkylene-NRaRb, —NRc-a lower alkylene- NRaRb, —N(alower alkylene-NRaRb)2, —CONRa—ORb, —NRa—CO—NRbRc, or —OCORb;

each of R2 and R3, which may be the same or different, represents —H, -alower alkyl, -a lower alkylene-ORa or -a lower alkylene-NRaRc, or R2 andR3 are combined together with the N atom adjacent thereto to form anitrogen-containing saturated heterocyclic group as —NR2R3 which mayhave one or more substituents;

each of Ra and Rc, which may be the same or different, represents —H or-a lower alkyl;

Rb represents —H, -a lower alkyl, a cycloalkyl, an aryl which may haveone or more substituents or a heteroaryl which may have one or moresubstituents;

n represents 0, 1, 2 or 3;

each of W and X, which may be same or different, represents N or CH;

Y represents O, S or NH; and,

R4 represents —H, -a lower alkyl, -a lower alkenyl, -a lower alkynyl,-(an aryl which may have one or more substituents), -a loweralkylene-(an aryl which may have one or more substituents), -a loweralkenylene-(an aryl which may have one or more substituents), -a loweralkynylene-(an aryl which may have one or more substituents), -(acycloalkyl which may have one or more substituents), -(a cycloalkenylwhich may have one or more substituents), -a lower alkylene-(acycloalkyl which may have one or more substituents), -a loweralkenylene-(a cycloalkyl which may have one or more substituents), -alower alkylene-(a nitrogen-containing saturated heterocyclic group whichmay have one or more substituents), -a lower alkenylene-(anitrogen-containing saturated heterocyclic group which may have one ormore substituents), -(a heteroaryl which may have one or moresubstituents), -a lower alkylene-(a heteroaryl which may have one ormore substituents), or -a lower alkenylene-(a heteroaryl which may haveone or more substituents). The same applies hereinbelow.

The compounds (I) of the present invention encompass the known compoundsas well as commercially available compounds later described in CompoundZ, which are all included within the definition of formula (I).

The present invention further relates to a novel fused heteroarylderivative represented by general formula (Ia) or (Ib) or salts thereof,as well as a novel pharmaceutical composition comprising the same and apharmaceutically acceptable carrier:

[wherein:

R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -acycloalkyl, -an aryl which may have one or more substituents, -aheteroaryl which may have one or more substituents, -a halogen, —NO2,—CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO— Rb, —COORb,—CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O— CO—NRaRbor —NRaCO—COORb, —CO-a nitrogen-containing saturated heterocyclic group,—CONRa-a lower alkyl-ORb, —CONRa-a lower alkylene-ORb, —O-a loweralkylene-NRb, —O-a lower alkylene-O-a lower alkylene-ORb, —O-a loweralkylene-NRaRb, —O-a lower alkylene-O-a lower alkylene-NRaRb, —O-a loweralkylene-NRc-a lower alkylene-NRaRb, —NRc-a lower alkylene-NRaRb, —N(alower alkylene-NRaRb)2, —CONRa—NRb, —NRa—CO—NRbRc, or —OCORb;

each of R2 and R3, which may be the same or different, represents —H or-a lower alkyl, or R2 and R3 are combined together with the N atomadjacent thereto to form a nitrogen-containing saturated heterocyclicgroup as —NR2R3 which may have one or more substituents;

Ra and Rc, which may be the same or different, represent —H or -a loweralkyl;

Rb represents —H, -a lower alkyl, a cycloalkyl, an aryl which may haveone or more substituents or a heteroaryl which may have one or moresubstituents;

n represents 0, 1, 2 or 3;

X represents N or CH;

Y represents O, S or NH; and,

R4a represents -(an aryl which may have one or more substituents), -alower alkylene-(an aryl which may have one or more substituents), -alower alkenylene-(an aryl which may have one or more substituents), -alower alkynylene-(an aryl which may have one or more substituents), -(acycloalkyl which may have one or more substituents), -(a cycloalkenylwhich may have one or more substituents), -a lower alkylene-(acycloalkyl which may have one or more substituents), -a loweralkenylene-(a cycloalkyl which may have one or more substituents), -alower alkylene-(a nitrogen-containing saturated heterocyclic group whichmay have one or more substituents), -a lower alkenylene-(anitrogen-containing saturated heterocyclic group which may have one ormore substituents), -(a heteroaryl which may have one or moresubstituents), -a lower alkylene-(a heteroaryl which may have one ormore substituents), or -a lower alkenylene-(a heteroaryl which may haveone or more substituents);

with the proviso that the following compounds are excluded:

(1) compounds in which X represents N, Y represents S, n is 3 and R1represents a combination of —CN, —OEt and phenyl, and R4a represents2-nitrophenyl;

(2) compounds in which X represents CH, and R4a represents -(aheteroaryl which may have one or more substituents);

(3) compounds in which X represents CH, Y represents O, n is 0 and R4arepresents an unsubstituted phenyl; and

(4) compounds in which X represents N, Y represents S, n is 2, R1represents an unsubstituted phenyl and R4a represents 4-methoxyphenyl oran unsubstituted phenyl. The same applies hereinbelow.

[wherein:

B represents a benzene ring, or a 5- or 6-membered monocyclic heteroarylcontaining 1 to 2 hetero atoms selected from O, S and N;

R1 represents -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -acycloalkyl, -an aryl which may have one or more substituents, -aheteroaryl which may have one or more substituents, -a halogen, —NO2,—CN, -a halogenated lower alkyl, —ORb, —SRb, —SO2-Rb, —SO— Rb, —COORb,—CO—Rb, —CONRaRb, —SO2NRaRb, —NRaRb, —NRa—CORb, —NRa—SO2Rb, —O—CO—NRaRb, —NRaCO—COORb, —NRaCOORb, —NRaCO-a lower alkylene-an aryl,—NRa—SO2- a lower alkylene-an aryl, —NRa-a lower alkylene-an aryl, -alower alkylene-ORb, -a lower alkylene-NRaRb, —CO-a nitrogen-containingsaturated heterocyclic group, —CONRa-a lower alkylene-ORb, —CONRa-alower alkylene-NRcRb, —CONRa-a lower alkylene-a nitrogen- containingsaturated heterocyclic group, —O-a lower alkylene-ORb, —O-a loweralkylene- NRaRb, —O-a lower alkylene-a nitrogen-containing saturatedheterocyclic group, —O-a lower alkylene-O-a lower alkylene-ORb, —O-alower alkylene-O-a lower alkylene-NRaRb, —O-a lower alkylene-NRc-a loweralkylene-NRaRb, —NRc-a lower alkylene-NRaRb, —N(a loweralkylene-NRaRb)2, —CONRa—ORb, —NRa—CO—NRbRc, or —OCORb;

R2 and R3 are combined together with the N atom adjacent thereto to form—NR2R3 which is a nitrogen-containing saturated heterocyclic group whichmay have one or more substituents;

Ra and Rc, which may be the same or different, represent —H or -a loweralkyl;

Rb represents —H, -a lower alkyl, -a cycloalkyl, -(an aryl which mayhave one or more substituents) or -(a heteroaryl which may have one ormore substituents);

n represents 0, 1, 2 or 3, whereas n represents 1, 2 or 3 when Brepresents a benzene ring;

W represents N or CH; and,

R4b represents-(an aryl which may have one or more substituents), -alower alkylene-(an aryl which may have one or more substituents), -alower alkenylene-(an aryl which may have one or more substituents), -alower alkynylene-(an aryl which may have one or more substituents), -(acycloalkyl which may have one or more substituents), -(a cycloalkenylwhich may have one or more substituents), -a lower alkylene-(acycloalkyl which may have one or more substituents), -a loweralkenylene-(a cycloalkyl which may have one or more substituents), -alower alkylene-(a nitrogen-containing saturated heterocyclic group whichmay have one or more substituents), -a lower alkenylene-(anitrogen-containing saturated heterocyclic group which may have one ormore substituents), -(a heteroaryl which may have one or moresubstituents), -a lower alkylene-(a heteroaryl which may have one ormore substituents), or -a lower alkenylene-(a heteroaryl which may haveone or more substituents);

with the proviso that the following compounds are excluded:

(1) 4-(4-morpholinyl)-2-phenylpyrido[2,3-d]pyrimidine,

(2) 4-(4-morpholinyl)-2-phenylpyrido[2,3-d]pyrimidin-7(1H)-one,

(3) 4-(4-morpholinyl)-2-pheny-6-quinazolinol and6-methoxy-4-(4-morpholinyl)-2-phenyquinazoline,

(4) 2,4-diamino-6-phenyl-8-piperidinopyrimido[5,4-d]pyrimidine,

(5) compounds in which B represents a benzene ring, W represents N, n is2 or 3, existing R1's all represent —OMe, and R4b is an unsubstitutedphenyl or a phenyl which is substituted by 1 to 3 substituents selectedfrom -halogen, —NO2, -a lower alkyl, —O-a lower alkyl, -a hanogenatedlower alkyl and —CONRaRc,

(6) compounds in which B represents a benzene ring, W represents N, n is1, R1 represents -halogen or -a lower alkyl, and R4b represents-(imidazolyl whch may have one or more substituents),

(7) compounds in which B represents a thiophene ring, and W representsCH,

(8) compounds in which B represents an imidazole ring, and W representsN,

(9) compounds in which B represents a pyridine ring, and R4b representsan unsubstituted phenyl, an unsubstituted pyridyl, or -a loweralkylene-(a nitrogen-containing saturated heterocyclic group which mayhave one or more substituents),

(10) compounds in which B represents a pyrazine ring, and R4b representsan unsubstituted phenyl, or a benzyl,

(11) compounds in which B represents a benzene ring, and R4b representsa styryl or 2-(5-nitro-2-furyl)vinyl, and

(12) compounds in which B represents a benzene ring, W represents CH,and R2 and R3 are combined together with the N atom adjacent thereto toform -(piperidinyl which may have one or more substituents) or-(piperazinyl which may have one or more substituents).

The same applies hereinbelow.

Further teaching of the present invention provides a method to treatdisorders (especially cancers) which are associated with PI3K, whereinthe method comprises of administering to a patient an effective amountof a fused heteroaryl derivative of formula (I), (Ia) or (Ib) above or asalt thereof as well as a use of said fused heteroaryl derivative or asalt thereof for producing a medicament (especially a carcinostaticagent) which inhibit PI3K.

Embodiments

The compounds of general formula (I), (Ia) or (Ib) are described belowin more detail.

The term “lower” throughout the specification is used to mean a straightor branched hydrocarbon chain having 1 to 10, preferably 1 to 6, andmore preferably 1 to 3 carbon atoms.

Preferred examples of the “lower alkyl” are an alkyl having 1 to 3carbon atoms, more preferably methyl and ethyl. Preferred examples ofthe “lower alkenyl” include vinyl, allyl, 1-propenyl, isopropenyl,1-butenyl, 2-butenyl and 3-butenyl. Preferred examples of the “loweralkynyl” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl and 1-methyl-2-propynyl. The terms “lower alkylene”, “loweralkenylene” and “lower alkynylene” are used to mean bivalent groups ofthe lower alkyl, lower alkenyl and lower alkynyl described above.Preferred examples of these groups are methylene, ethylene, vinylene,propenylene, ethynylene and propynylene. The terms “cycloalkyl” and“cycloalkenyl” refer to cycloalkyl and cycloalkenyl groups preferablyhaving 3 to 8 carbon atoms. Preferred examples of these groups includecyclopropyl, cyclopentyl, cyclohexyl and cyclopentenyl.

Examples of the “halogen” are F, Cl, Br and I. Examples of the“halogenated lower alkyl” are the aforementioned lower alkyl groupswhich are further substituted with one or more halogen atoms describedabove, preferably —CF3.

The term “nitrogen-containing saturated heterocyclic group” throughoutthe specification refers to a 5- to 7-membered heterocyclic groupcontaining one or two nitrogen atoms on the ring, which may furthercontain one O or S atom and may form a bridge structure or may be fusedwith one benzene ring. Preferred examples of such heterocyclic group arepyrrolidinyl, piperazinyl, piperidyl and morpholinyl. Preferred examplesof the nitrogen-containing saturated heterocyclic group as —NR2R3 are1-pyrrolidinyl, 1-piperazinyl, piperidino and morpholino, withparticular preference to morpholino.

The term “aryl” is used throughout the specification to mean an aromaticcyclic hydrocarbon group. An aryl having 6 to 14 carbon atoms ispreferable. Preferred examples of such aryl are phenyl and naphthyl.

The term “heteroaryl” refers to a 5- or 6-membered monocyclic heteroarylcontaining 1 to 4 hetero atoms selected from N, S and O as well as abicyclic heteroaryl fused to a benzene ring. The heteroaryl may bepartially saturated. Preferred examples of the monocyclic heteroaryl arefuryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl and pyrazinyl. Examples of the bicyclic heteroaryl arepreferably benzofuranyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl,quinolyl, isoquinolyl, cinolinyl, quinazolinyl, quinoxalinyl andbenzodioxolyl. Specific examples of the partially saturated heteroarylare 1,2,3,4-tetrahydroquinolyl, etc. Particularly preferred are 5- to6-membered monocyclic groups, more preferably imidazolyl, thiazolyl,triazolyl, pyridyl and pyrazinyl.

Examples of a “5- or 6-membered monocyclic heteroaryl containing 1 or 2hetero atoms selected from O, S and N” in B include a furan, thiophene,pyrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, pyridine,pyrimidine, pyridazine and pyrazine ring. Preferably, it is a pyridine,pyrazine or thiophene ring. More preferable, it is a pyridine ring.

The substituents for the “aryl which may have one or more substituents”,“heteroaryl which may have one or more substituents”, “cycloalkyl whichmay have one or more substituents”, “cycloalkenyl which may have one ormore substituents” or “nitrogen-containing saturated heterocyclic groupwhich may have one or more substituents” are 1˜5 substituents, which maybe the same or different. Preferably, these substituents are selectedfrom Group A described below. Each of R, R′ and R″, which may be thesame or different, represents H or a lower alkyl (the same shall applyhereinafter).

Group A: -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a halogen,-a halogenated lower alkyl, -a lower alkylene-OR, —NO2, —CN, ═O, —OR, —Oa halogenated lower alkyl, —O-a lower alkylene-NRR′, —O-a loweralkylene-OR, —O-a lower alkylene-an aryl, —SR, —SO2-a lower alkyl, —SO-alower alkyl, —COOR, —COO-a lower alkylene-an aryl, —COR, —CO-an aryl,-an aryl, —CONRR′, —SO2NRR′, —NRR′, —NR″-a lower alkylene-NRR′, —NR′-alower alkylene-OR, —NR-a lower alkylene-an aryl, —NRCO-a lower alkyl,—NRSO2-a lower alkyl, -a cycloalkyl and -a cycloalkenyl.

When R4, R4a and R4b represent “an aryl which may have one or moresubstituents” or “a heteroaryl which may have one or more substituents”,the substituents are 1 to 5 groups selected from a) through c) below,which may be the same or different.

a): -a lower alkyl, -a lower alkenyl, -a lower alkynyl, -a halogen, -ahalogenated lower alkyl, -a lower alkylene-OR, —NO2, —CN, ═O,—O-halogenated lower alkyl, —SO2-a lower alkyl, —SO-a lower alkyl,—COOR, —COO-a lower alkylene-an aryl, —COR, —CO-an aryl, —CONRR′,—SO2NRR′, -Cyc or -Alp-Cyc (wherein Alp represents a lower alkylene, alower alkenylene or a lower alkynylene, and Cyc represents an aryl whichmay have 1 to 5 substituents selected from Group A, a heteroaryl whichmay have 1 to 5 substituents selected from Group A, anitrogen-containing saturated heterocyclic group which may have 1 to 5substituents selected from Group A, a cycloalkyl which may have 1 to 5substituents selected from Group A, or a cycloalkenyl which may have 1to 5 substituents selected from Group A; the same shall applyhereinafter).

b): —NR-E-F (wherein E represents —CO—, —COO—, —CONR′—, —SO2NR′— or—SO2-; F represents -Cyc or -(a lower alkyl, a lower alkenyl or a loweralkynyl which may be substituted by one or more substituents selectedfrom the group comprising of -a halogen, —NO2, —CN, —OR, —O-a loweralkylene-NRR′, —O-a lower alkylene-OR, —SR, —SO2-a lower alkyl, —SO-alower alkyl, —COOR, —COR, —CO-an aryl, —CONRR′, —SO2NRR′, —NRCO-a loweralkyl, —NRR′, —NR′-a lower alkylene-OR, —NR″-a lower alkylene-NRR′ and-Cyc); and the same shall apply hereinafter).

c): -Z-R′, -Z-Cyc, -Z-Alp-Cyc, -Z-Alp-Z′-R′ or -Z-Alp-Z′-Cyc (whereineach of Z and Z′, which may be the same or different, independentlyrepresents O, S or NR; and the same shall apply hereinafter).

The particularly preferred ones are -a lower alkylene-OR, —CONRR′,—NR-CO-Cyc1 (wherein Cyc1 is -an aryl which may have 1˜5 substituentsselected from Group A, -a heteroaryl which may have 1˜5 substituentsselected from Group A, or -a nitrogen- containing saturated heterocyclicgroup which may have 1˜5 substituents selected from Group A, and thesame applies hereinbelow), —NR—SO2-Cyc1, —OR, —NRR′, —O-a loweralkylene-NRR′ and —O-a lower alkylene-(a nitrogen-containing saturatedring which may have 1˜5 substituents selected from Group A).

When n is 2 to 4, each R1 group may be the same or different,independently.

In the compounds which are shown by formulas (I), (Ia) and (Ib) of thepresent invention, the following compounds are preferred:

(1) Compounds in which R2 and R3 forms —NR2R3 which is anitrogen-containing saturated heterocyclic group which may have 1˜2substituents selected from the group comprising of —OH, ═O and -a loweralkyl;

(2) Compounds in which R2 and R3 forms —NR2R3 which is -morpholino;

(3) Compounds in which W is N;

(4) Compounds in which R4, R4a or R4b represents -(an aryl which mayhave one or more substituents) or -(a heteroaryl which may have one ormore substituents);

(5) Compounds in which B represents a benzene ring; R1 represents -alower alkyl, -a lower alkenyl, -a lower alkynyl, -a cycloalkyl, -an arylwhich may have one or more substituents, -a heteroaryl which may haveone or more substituents, -a halogen, —NO2, —CN, -a halogenated loweralkyl, —ORb, —SRb, —SO2-Rb, —SO—Rb, —COORb, —CO—Rb, —CONRaRb, —SO2NRaRb,—NRaRb, —NRa—CORb, —NRa—SO2Rb, —O—CO—NRaRb or —NRaCO—COORb;

(6) Compounds in which B is a pyridine, pyrazine or thiophene ring and nis 0;

(7) Compounds in which X represents N, Y represents O and n is 0; and

(8) Compounds in which R4, R4a or R4b represents an aryl which has oneor more substituents selected from the group comprising of -a loweralkylene-OR, —CONRR′, —NR—CO-Cyc1, —NR—SO2-Cyc1, —OR, —NRR′, —O-a loweralkylene-NRR′ and —O-a lower alkylene- (a nitrogen-containing saturatedheterocyclic group which may have 1˜5 substituents selected from GroupA).

The particularly preferred compounds shown by general formula (Ia) arethose having R4a which is a phenyl having at least one substituent whichis selected from of the group comprising of —OH, —NH2, —NH-a loweralkyl, —N(a lower alkyl)2, —O-a lower alkylene-NH2 and —O-a loweralkylene-(a nitrogen-containing saturated heterocyclic group which maybe substituted by a lower alkyl).

Moreover, the following compounds shown by general formula (Ib) areparticularly preferred:

(1) Compounds in which W represents N, R4b represents -(an aryl whichmay have one or more substituents), and R2 and R3 form —NR2R3 which is-morpholino;

(2) Compounds in which B represents a benzene ring, n is 1 or 2, and R1represents -a halogen, —NO2, —CN, -a halogenated lower alkyl, —ORb,—SRb, —NRaRb, —NRa—CORb or —NRa—SO2Rb; and

(3) Compounds in which B represents a pyridine, pyrazine or thiophenering, n is 0, and R4b represents a phenyl which has at least onesubstituent which is selected from —OH, —CH2OH and —CONH2.

Among the compounds of the present invention, the preferred ones whichare shown by general formula (Ia) are (Co 17)6-amino-3′-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)nicotinanilide,(Co 33)4-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)aniline, (Co50) 3-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol,(Co 69)4-morpholino-2-[3-(2-piperazin-1-ylethoxy)phenyl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine,(Co 73)3′-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)acrylanilide,and salts thereof. The preferred ones which are shown by general formula(Ib) are (Co 144)N-[2-(3-benzenesulfonylaminophenyl)-4-morphoniloquinazolin-6-yl]acetamide,(Co 164) 3-(4-morpholinopyrido[4,3-d]pyrimidin-2-yl)phenol, (Co 172)3-(4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenol, (Co 174)3-(4-morpholinopyrido[3,4-d]pyrimidin-2-yl)phenol, (Co 186)3-(6-methoxy-4-morpholinoquinazolin-2-yl)phenol, (Co 190)3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol, (Co 191)3-(4-morpholinopteridin-2-yl)phenol, and salts thereof.

The compound of this invention may exist in the form of geometricalisomers or tautomers depending on the kinds of substituent groups, andthese isomers in separated forms or mixtures thereof are included in thepresent invention. Also, the compound of the present invention may haveasymmetric carbon atoms, so that optical isomer forms may exist based onsuch carbon atoms. All of the mixtures and the isolated forms of theseoptical isomers are included in the present invention.

Some of the compounds of the invention may form salts. There is noparticular limitation so long as the formed salts are pharmacologicallyacceptable. Specific examples of acid salts are salts with inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,aspartic acid, glutamic acid, etc. Specific examples of basic saltsinclude salts with inorganic bases containing metals such as sodium,potassium, magnesium, calcium, aluminum, etc., or salts with organicbases such as methylamine, ethylamine, ethanolamine, lysine, ornithine,etc. In addition, various hydrates and solvates and polymorphism of thecompound (I), (Ia) or (Ib) and salts thereof are also included in thisinvention.

(Processes for producing compounds)

Hereinafter representative processes for producing the compounds of thepresent invention are described below. In these processes, functionalgroups present in the starting materials or intermediates may besuitably protected with protective groups, depending upon the kinds offunctional groups. In view of the preparation technique, it may beadvantageous to protect the functional groups with groups that can bereadily reverted to the original functional groups. When required, theprotective groups are removed to give the desired products. Examples ofsuch functional groups are amino, hydroxy, carboxyl, etc. Examples ofthe protective groups which may be used to protect these functionalgroups are shown in, e.g., Greene and Wuts, “Protective Groups inOrganic Synthesis”, second edition. These protective groups may beappropriately employed depending upon reaction conditions.

Production Method 1

(Here and hereinafter, L represents a leaving group.)

This process for producing the compounds (I) of the present inventioncomprises converting the compounds shown by general formula (II) toreactive derivatives thereof (III) in a conventional manner and thenreacting an amine (IV) with the reactive derivatives. When anotherreactive site containing the leaving group L also exists on the ring Aor the substituent R4 in the reactive derivatives (III), the same ordifferent amine (IV) may be reacted again, if necessary. In a similarmanner, when the A ring or R4 of the compounds of the present inventionhas a leaving group L such as a chloro or fluoro, transformations offunctional groups may be conducted such as a hydrolysis reactionaccording to a method described in J. Am. Chem. Soc., 68, 1288 (1946) oran ipso-substitution reaction using alkoxide as a reacting agentaccording to a method described in Tetrahedron Lett., 40, 675 (1999).

The leaving group shown by L is preferably a halogen, or an organicsulfonyloxy group, e.g., methanesulfonyloxy, p-toluenesulfonyloxy, etc.

The reaction for preparing the reactive derivatives (III) can be carriedout by the usual procedures. Where the leaving group is chlorine,phosphorus oxychloride, oxalyl chloride or thionyl chloride can bereacted under cooling or heating or at room temperature in an inertorganic solvent or without. As such an inert organic solvent, there isan aromatic hydrocarbon solvent such as benzene or toluene; an etherealsolvent such as tetrahydrofitran (THF), 1,4-dioxane, etc.; a halogenatedhydrocarbon solvent such as dichloromethane, chloroform, etc.; and abasic solvent such as pyridine or collidine. These solvents may be usedalone or as a mixture of two or more. The solvent is optionally selecteddepending on the kinds of starting compounds. The addition of a base(preferably a dialkylaniline, triethylamine, ammonia, lutidine,collidine, etc.), phosphorus chloride (e.g., phosphorus pentachloride),a quaternary ammonium salt (e.g., tetraethylammonium chloride), or anN,N-dialkylamide compound (e.g., dimethylformamide (DMF)) may beadvantageous in some cases from the viewpoint of accelerating thereaction. Where the leaving group is sulfonyloxy, the activeintermediates (III) can be synthesized from the corresponding sulfonylchloride by the usual procedures, e.g., using a method described inTetrahedron Lett. 23 (22), 2253 (1982) or Tetrahedron Lett. 27 (34),4047 (1986).

The reaction for producing the compounds (I) from the reactivederivatives (III) and the amine (IV) can be carried out by reacting theamine (IV) in an inert organic solvent or in the absence of any solventsunder cooling or heating or at room temperature. The solvent describedabove is available and it may be used singly or as a mixture of two ormore. The addition of an inorganic base such as sodium hydride, or anorganic base such as triethylamine (TEA), pyridine or 2,6-lutidine, maybe advantageous in some cases from the viewpoint of accelerating thereaction

Production Method 2

(Wherein Rd is a lower alkyl which may have one or more substituents andRb has the same definition as defined above; and the same shall applyhereinafter.)

This process comprises O-alkylation of the hydroxy-substituted compoundsshown by general formula (Ia) or (Ic) in a conventional manner to obtainthe compounds (Ib) or (Id). The reaction may be carried out, e.g., byreacting the compounds (Ia) or (Ic) with an alkylating agent such as analkyl halide or a sulfonic acid ester in the presence of a base such astriethylamine, potassium carbonate, sodium carbonate, cesium carbonate,sodium hydroxide, sodium hydride or potassium t-butoxide. The reactiontemperature can be under cooling or heating or at room temperature, andcan be appropriately chosen depending on the kinds of startingcompounds. When water is used or contained as a solvent in anO-alkylation reaction, the reaction may be accelerated by the additionof a phase transfer catalyst such as tetra n-butylammoniumhydrogensulfate.

Another method for the O-alkylation reaction is Mitsunobu reaction. Forexample, methods described in Synthesis, 1 (1981) or modified methodsmay be used. For the hydroxyethylation of a hydroxyl group, methodsusing carbonate ester such as [1,3]dioxolane-2-one are also effective.As an example, methods described in J. Am. Chem. Soc., 68, 781 (1946)can be used.

Moreover, when functional groups exist on Rb and Rd of the compounds(Ib) and (Id) of the present invention, known reactions may be employedto convert the functional group. For example, when a hydroxyl group ispresent on Rb and Rd, the aforementioned O-alkylation reaction can beconducted, and when a leaving group is present such as a halogen, anappropriate alcohol or amine can be reacted with utilizing theconditions of said O-alkylation or N-alkylation described hereinafter inProduction Method 4. When an ester group is present, the functionalgroup can be converted to a carboxylic acid, hydroxymethyl group, andamido, using a method described hereinafter in Production Method 3.

The starting compounds (Ia) and (Ic) used in this process can beprepared by the method described for Production Method 1, using startingcompounds whose OH group has been protected by an acyl type protectivegroup (e.g., acetyl or tosyl). Further, when phosphorus oxychloride isused as a reacting agent for synthesizing reactive derivatives (III) andthen a desired amino is reacted to synthesize (I), protective groups forOH group may be removed and O-phosphoramides may be produced, dependingon the kind of starting compounds, a protective group, reactionconditions and conditions for work-up. In that case, for example, usinga method described in Chem. Pharm. Bull.,37, 2564 (1989), phosphoramidesgroups can be removed. Other general protective groups can be introducedand removed by the methods described in “Protective Groups in OrganicSynthesis” supra.

Production Method 3

(Wherein Rf is a lower alkyl and Rg is a lower alkyl which may have oneor more substituents; and the same shall apply hereinafter.)

Production Method 3 comprises transformations of the functional groupsof the ester compounds of the present invention shown by general formula(Ie) to produce the hydroxymethyl compounds (If), carboxylic acidderivatives (Ig) and amide derivatives (Ih) of the present invention,respectively. Each of the reactions can be carried out in a conventionalmanner, e.g., as described in Jikken Kagaku Kouza (Encyclopedia forExperimental Chemistry) edited by Nihon Kagaku Kai (Japanese Associationof Chemistry) and published by Maruzen Co., Ltd., and “Protective Groupsin Organic Synthesis” supra.

Preferably, the reduction to give the hydroxymethyl compounds (If) canbe conducted in an inert organic solvent to the reactions, e.g., anethereal solvent or an aromatic hydrocarbon solvent, using a reducingagent such as lithium aluminum hydride, lithium borohydride, zincborohydride, boran, Vitride, etc. The hydrolysis to give the carboxylicacid derivatives (Ik) can be conducted by reacting with lithiumhydroxide, sodium hydroxide or potassium hydroxide in a single solventselected from methanol, ethanol, THF and water, or a mixture of two ormore. The amidation to give the amide compounds (Ih) may be performed byconverting carboxylic acids to reactive derivatives such as acyl halides(acyl chlorides, etc.) or acid anhydrides, and then reacting thereactive derivatives with amines. In the reaction with amines, it ispreferred to conduct the reaction in an inert organic solvent in thepresence of a base (an inorganic base such as sodium hydroxide, or anorganic base such as TEA, diisopropylethylamine or pyridine).Furthermore, the amidation using the carboxylic acid as a startingcompound can also be carried out in an inert organic solvent in thepresence of a condensation agent such as(1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI),1,1′-carbonylbis-1H-imidazole (CDI), etc.). In this case, an additivesuch as 1-hydroxybenzotriazol (HOBt) or the like may also be added tothe reaction. The reaction temperature and solvent can be appropriatelychosen depending on the kinds or the like of starting compounds.

Production Method 4

(Wherein R′ has the same definition as defined above, Rh is -a loweralkyl which may have one or more substituents, Ri is -Cyc or -Alp whichmay have one or more substituents, a C ring is a nitrogen-containingsaturated heterocyclic group which may have one or more substituents,and Rj is —H, -a lower alkyl, -an aryl, etc.; and the same shall applyhereinafter.)

Production Method 4 comprises the reduction of the nitro compounds shownby general formula (Ii) to the corresponding amino compounds (Ij) andthen subjecting the amino compounds (Ij) to various modificationreactions including N-alkylation, amidation, sulfonamidation, conversionto the corresponding urea, conversion to the corresponding carbamicacid, imidation or conversion to the corresponding thiazoles, to givethe compounds (Ik), (Im), (In), (Io), (Ip), (Iq) and (Ir), respectively.These products can be appropriately subjected to further knownmodification reactions such as N-alkylation, if necessary.

These reactions can all be carried out in a conventional manner, e.g.,using the methods described in “Jikken Kagaku Kouza” supra, or“Protective Groups in Organic Synthesis” supra. Preferred procedures inthese methods are described below.

The reduction of the nitro compounds can be carried out in an alcoholicsolvent such as methanol in a gaseous hydrogen atmosphere usingpalladium on carbon (Pd—C).

When various aldehydes are employed as the starting compounds, theN-alkylation can be conducted by reductive amination using aldehydes andreducing agents such as sodium borohydride, sodium triacetoxyborohydrideor sodium cyanoborohydride. Reducting amination using Dean-Starkapparatus could be useful, too. When an alkyl halide such as methyliodide or benzyl bromide, or dimethyl sulfate is employed as analkylating agent, the reaction can be carried out in an inert organicsolvent, e.g., DMF, acetonitrile or toluene, in the presence of basesuch as potassium carbonate, sodium hydroxide or sodium hydride, undercooling or heating or at room temperature. For monoalkylation, anexample of useful procedure is as follows: protection of amino group byacyl group such as trifluoroacetyl, alkylation of acylamide byconventional methods using halogenated alkyl, and removal of protection.The dialkylation can be conducted by reacting 2 equivalents or more of ahalogenated alkyl. For dimethylation, the reaction with formalin informic acid at room temperature or under heating is also useful.

The amidation reaction may be performed in a similar manner to thatdescribed above for Production Method 3. The sulfonamidation can becarried out in an inert organic solvent using a reactive derivative suchas an acid halide (acid chloride, etc.) or an acid anhydride. Theconversion to the corresponding urea can be conducted by reacting withisocyanates in an inert organic solvent, e.g., an aromatic hydrocarbonsolvent, under cooling or heating or at room temperature. The conversionto the corresponding carbamic acids can be conducted by reactingchloroformate derivatives in an inert organic solvent under cooling orheating or at room temperature. The imidation can be carried out usingagents such as succinic anhydride or maleic anhydride.

The conversion to the corresponding aminothiazole compounds can beconducted by converting the amino compounds to the correspondingthiourea derivatives and then reacting the derivatives with anα-halogenated ketone. Compounds (Ij) can be converted into the thioureaderivatives by methods described in, e.g., Synth. Commun. 1998, 28 (8),1451; J. Org. Chem., 1984, 49 (6), 997, Org. Synth., 1963, IV, 180; J.Am. Chem. Soc., 1934, 56, 1408, etc. The conversion of the thioureaderivatives into the thiazole derivatives can be conducted by reactingthe thiourea derivatives with the α-halogenated ketone in an alcoholicsolvent such as ethanol or a carbonyl solvent such as methyl ethylketone, under cooling or heating or at room temperature. The addition ofa base (potassium carbonate, sodium carbonate, etc.) may be effective insome cases from the viewpoint of accelerating the reaction.

Production Method 5

(Wherein Rk and Rm each represents -a lower alkyl which may have one ormore substituents.)

Production Method 5 comprises converting the nitro compounds of theinvention shown by general formula (Is) to the corresponding aminocompounds (It) and then subjecting them to various modificationreactions to obtain the other compounds of the present invention. Eachreaction can be carried out as described for Production Method 4.

Other Production Method

Other compounds included in the present invention can be obtained in thesame manner as described above or by using methods well known to thoseskilled in the art. For instance, the reactions are carried outappropriately using methods described in “Jikken Kagaku Kouza” supra, or“Protective Groups in Organic Synthesis” supra.

For example, the demethylation reaction of compounds with an aryl groupinto the corresponding phenol derivatives can be carried out by themethods described in “Protective Groups in Organic Synthesis” supra,i.e., the method of reacting with a demethylating agent such as sodiumcyanide or potassium cyanide in a solvent such as dimethylsulfoxide(DMSO), etc., at room temperature or under heating.

Processes for Preparing Starting Compounds

The starting compounds (II) for the synthesis of the present inventioncan be performed in conventional manners, e.g., by the reactions shownin the following synthetic routes.

Process 1

(Wherein Rn is a lower alkyl; and the same shall apply hereinafter.)

The starting compounds (IIc) can be synthesized by a cyclizationreaction of amide intermediates (5) or cyclization conducted by reactinganthranylic acid derivatives (1) as the starting compounds with imidates(6). Conventional cyclization reactions for preparing pyrimidine ringare available for the cyclization reaction for this purpose. Forinstance, the method described in Chem. Pharm. Bull., 39 (2), 352 (1991)can be used for the cyclization of the intermediates (5) and theintermediates (1) and (6) as the starting materials can be cyclized bythe method described in J. Med. Chem., 9, 408 (1966). The amideintermediates (5) can be synthesized by amidation of the anilinederivatives (4) in a conventional manner, or by sequential conversionsof esterification of a carboxylic acid in (1), acylation of an amino,and amidation of the ester group according to conventional methods. Forexample, the amide intermediates (5) can be obtained in accordance withthe methods described in J. Med. Chem., 33, 1722 (1990), Eur. J. Med.Chem.-Chim. Ther., 9(3), 305 (1974), etc. When (3) is obtained byacylation using (2) as the starting materials, diacylation may takeplace depending on the starting compounds and reaction conditions. Insuch a case, treatment with basic conditions will give desired monoacylcompounds (3).

Process 2

The starting compounds (IId) can be synthesized by cyclization of theamide intermediates (12) or by cyclization of the ester intermediates(7) and the amide compounds (10). The intermediates (12) can be cyclizedin the same manner as described above; where the intermediates (7) and(10) are used as the starting compounds, the cyclization can be carriedout by the method described in, e.g., J. Med. Chem., 37, 2106 (1994).The amide intermediates (12) can be prepared by conversion of thefunctional group in ester compounds (7) in a conventional manner. Thebicyclic ester intermediates (9) can be synthesized by formation of a5-membered ring by reacting nitrile compounds (7) with ester compounds(8) in the presence of a base, for example, in accordance with themethod described in J. Org. Chem., 37, 3224 (1972) or J. Heterocycl.Chem., 11 (6), 975 (1974), etc.

Process 3

The starting compounds (IIe) can be synthesized, e.g., by cyclization ofthe starting compounds (14). Preferably, the compounds (14) are heatedin a solvent with a high boiling point such as diphenyl ether or in theabsence of any solvents. The starting compounds (14) can be synthesizedin a conventional manner, e.g., by. condensation of the correspondinganilines (13) with the compounds (15).

Each of the reaction products obtained by the aforementioned productionmethods is isolated and purified as a free base or a salt thereof. Thesalt can be produced by a usual salt forming method. The isolation andpurification are carried out by employing usually used chemicaltechniques such as extraction, concentration, evaporation,crystallization, filtration, recrystallization, various types ofchromatography and the like.

Various forms of isomers can be isolated by the usual procedures makinguse of physicochemical differences among isomers. For instance, racemiccompounds can be separated by means of a conventional optical resolutionmethod (e.g., by forming diastereomer salts with a conventionaloptically active acid such as tartaric acid, etc. and then opticallyresolving the salts) to give optically pure isomers. A mixture ofdiastereomers can be separated by conventional means, e.g., fractionalcrystallization or chromatography. In addition, an optical isomer canalso be synthesized from an appropriate optically active startingcompound.

Industrial Applicability

The compounds of the present invention exhibit a PI3K inhibitoryactivity and therefore, can be utilized in order to inhibit abnormalcell growths in which PI3K plays a role. Thus, the compounds areeffective in the treatment of disorders with which abnormal cell growthactions of PI3K are associated, such as restenosis, atherosclerosis,bone disorders, arthritis, diabetic retinopathy, psoriasis, benignprostatic hypertrophy, atherosclerosis, inflamation, angiogenesis,immunological disorders, pancreatitis, kidney disease, cancer, etc. Inparticular, the compounds of the present invention possess excellentcancer cell growth inhibiting effects and are effective in treatingcancers, preferably all types of solid cancers and malignant lymphomas,and especially, leukemia, skin cancer, bladder cancer, breast cancer,uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer,pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.

The pharmacological effect of the compounds according to the inventionhave been verified by the following pharmacological tests.

Test Example 1 Inhibition of PI3K (p110α subtype)

Inhibition was determined using enzyme (bovine p110α) prepared in thebaculovirus expression system. Bovine p110 was prepared according to amodification from the method by I. Hiles et al., Cell, 70, 419 (1992).Each compound to be assayed was dissolved in DMSO and the obtained 10 mMDMSO solution was serially diluted with DMSO.

The compound (0.5 μl) to be assayed and enzyme were mixed in 25 μl ofbuffer solution (40 mM Tris-HCl (pH 7.4), 200 mM NaCl, 2 mMdithiothreitol, 5 mM MgCl2). Then, 25 μl of 5 mM Tris-HCl (pH 7.4)buffered solution supplemented with 10 μg PI (Sigma), 2μ Ci [γ-32P] ATP(Amersham Pharmacia) and 80 μM non-radiolabeled ATP (Sigma) was added tothe mixture to initiate the reaction. After reacting at 37° C. for 15minutes, 200 μl of 1M HCl and 400 μl of CHCl3/MeOH (1:1) were added tothe reaction mixture. The resulting mixture was stirred and thencentrifuged. After the organic layer was again extracted twice with 150μl of MeOH/1M HCl (1:1). The radioactivity was measured using Cerenkovlight.

The IC50 inhibition activity was defined by a 50% inhibitionconcentration of each compound assayed, which was converted from theradioactivity determined as 100% when DMSO alone was added and as 0%when no enzyme was added.

The compounds of the prevent invention exhibited an excellent p110αsubtype inhibition activity. For example, IC50 of Compound (hereinafter,abbreviated as Co) 10, Co 17, and Co 24 were less than 1 μM.

Moreover, compounds of the prevent invention were confirmed to haveinhibiting activities against other subtypes (such as a C2 β subtype).

Test Example 2Colon Cancer Cell Growth Inhibition

HCT116 cells from a colon cancer cell line were cultured in McCoy's 5Amedium (GIBCO) supplemented with 10% fetal bovine serum. HCT116 cellswere inoculated on a 96 well plate (5000 cells/well) followed byovernight incubation. The test compound diluted with the medium wasadded to the medium in a final concentration of 0.1 to 30M (final DMSOconcentration, 1%). After incubation over 72 hours, Alamar Blue reagentwas added to the medium. Two hours after the addition, a ratio offluorescent intensity at an excitation wavelength of 530 nm to that atan emission wavelength of 590 nm was measured to determine the IC50. Co14, Co 24, Co 25, Co 31, Co 46 and Co 47 of the present inventionexerted an excellent cancer cell growth inhibition activity.

Test Example 3Melanoma Cell Growth Inhibition

A375 cells from a melanoma cell line were cultured in DMEM medium(GIBCO) supplemented with 10% fetal bovine serum. A375 cells at 10,000cells/100 μl were added to a 96 well plate which contained 1 μl/well ofthe test compounds (final concentration of 0.001˜30 μM). Afterincubation for over 46 hours, Alamar Blue reagent was added to themedium (10 μl/well). Two hours after the addition, a ratio offluorescent intensity at an excitation wavelength of 530 nm to that atan emission wavelength of 590 nm was measured to determine the IC50 ofthe test compounds in the same manner as in the above examples.

The compounds of the prevent invention exhibited an excellent cancercell growth inhibition activity. For example, Co17, Co 33, Co 50, Co 69,Co 164, Co 172, Co 174, Co 186, Co 190 and Co 191 exerted a goodmelanoma cell growth inhibition activity. Their IC50 values were0.33˜4.26 μM. Contrarily, the known PI3K inhibitor LY294002 showed avalue of 8.39 μM.

In addition to the above cancer cell lines, the compounds of the presentinvention exhibited excellent cancer cell growth inhibiting activitiesagainst Hela cells from a cervix cancer cell line, A549, H460 cells froma lung cancer cell line, COLO205, WiDr, Lovo cells from a colon cancercell line, PC3, LNCap cells from a prostate cancer cell line, SKOV-3,OVCAR-3, CH1 cells from an ovary cancer cell line, U87 MG cells from aglioma cell line and BxPC-3 cells from a pancreas cancer cell line.

Test Example 4In vivo Cancer Cell Growth Inhibition

A single-cell suspension of HelaS3 (5×106 cells), a human cervix cancercell line, was inoculated into the flank of female Balb/c nude mice bysubcutaneously injection. When the tumor reached 100˜200 mm3 in volume,test compounds were intraperitoneally administered once a day for twoweeks. 20% Hydroxypropyl-β-cyclodextrin/saline was intraperitoneallyadministered with the same schedule as a control group. The diameter ofthe tumors was measured with a vernier caliper at certain time intervalsuntil one day after the final doze administration. The tumor volume wascalculated by the following formula: ½×(a shorter diameter)2×(a longerdiameter).

In the present test, test compounds exhibited superior anti-tumoractivities as compared with the control group.

The pharmaceutical composition of the present invention can be preparedin a conventional manner by mixing one or more compounds of theinvention shown by general formula (I) with a carrier for medical use, afiller and other additives usually used in pharmaceutical preparation.The pharmaceutical composition of the invention may be administeredeither orally in the form of tablets, pills, capsules, granules,powders, liquid, etc., or parenterally such as by intravenous orintramuscular injection, in the form of suppositories, or throughpernasal, permucosal or subcutaneous route.

For oral administration of the composition in the present invention, asolid composition in the form of, e.g., tablets, powders or granules isavailable. In such a solid composition, one or more active or effectiveingredients are blended with at least one inert diluent such as lactose,mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose,starch, polyvinyl pyrrolidone or magnesium aluminate metasilicate. Thecomposition may further contain additives other than the inert diluentby the usual procedures. Examples of such additives include a lubricantsuch as magnesium stearate, a disintegrating agent such as calciumcellulose glycolate, a solubilization assisting agent such as glutamicacid or aspartic acid. Tablets or pills may be coated, if necessary,with films of sugar or a gastric or enteric substance such as sucrose,gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulosephthalate, etc.

A liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, etc. andcontains an inert diluent conventionally employed, e.g., purified wateror ethanol. In addition to the inert diluent above, the liquidcomposition may further contain an auxiliary agent such as a moisteningagent or a suspending agent, a sweetener, a flavor and/or apreservative.

A composition for parenteral administration contains a sterile aqueousor non-aqueous solution, a suspension and an emulsion. Examples of theaqueous solution and suspension include distilled water for injectionuse and physiological saline. Typical examples of the non-aqueoussolution and suspension are propylene glycol, polyethylene glycol,vegetable oil such as olive oil, an alcohol such as ethanol, polysorbate80, and the like. These compositions may further contain a preservative,a moistening agent, an emulsifier, a dispersing agent, a stabilizer anda solubilization assisting agent. These compositions are sterilized,e.g., by filtering them through a bacteria retention filter,incorporating a bactericide or through irradiation. Alternatively, theymay be prepared into a sterile solid composition, which is dissolved insterile water or a sterile solvent for injection prior to use.

In the case of oral administration, suitable daily does is usually about0.0001 to 50 mg/kg body weight, preferably about 0.001 to 10 mg/kg, morepreferably about 0.01 to 1 mg/kg, and the daily does is administeredonce a day or divided into 2 to 4 doses per day. In the case ofintravenous injection, suitable daily dose is usually about 0.0001 to 1mg/kg body weight, preferably about 0.0001 to 0.1 mg/kg. And the dailydoes is administered once a day or divided into a plurality of doses perday. The dose may be appropriately determined for each case, dependingon conditions, age, sex, etc.

The compounds of the present invention can be utilized alone, or inconjunction with other treatments (e.g., radiotherapy and surgery).Moreover, they can be utilized in conjunction with other antitumoragents, such as alkylation agents (cisplatin, carboplatin, etc.),antimetabolites (methotrexate, 5-FU, etc.), antitumor antibiotics(adriamymycin, bleomycin, etc.), antitumor vegetable alkaloids (taxol,etoposide, etc.), antitumor hormones (dexamethasone, tamoxifen, etc.),antitumor immunological agents (interferon α, β, γ, etc.), and so forth.

EXAMPLES

The present invention will be described in more detail by referring tothe following EXAMPLES but is not deemed to be limited thereto.

The following Tables 1˜3 and 13˜16 show starting compounds which wereused in EXAMPLES, and Tables 4˜11 and 17˜24 show structural formulas aswell as physicochemical properties of the compounds of the presentinvention. Moreover, the compounds of the present invention withstructural formulas shown in Tables 12 and 25˜26 can be easily producedin the same manner as in the EXAMPLES mentioned hereinafter or inaccordance with the Production Methods mentioned hereinabove, or byapplying thereto some modifications which are obvious to those skilledin the art.

In the tables, abbreviations are used to mean the following.

Rco:starting compounds number

Rex:Production method of Reference Example compounds (a following numberrepresents a Reference Example number described hereinafter, indicatingthat the compound was prepared using the method described in theReference Example or the one similar thereto.)

Co:compounds number of the present invention

Str:structural formula

Sal:salt

Syn:production method (a following number represents a number of anEXAMPLE described hereinbelow, indicating that the associated compoundis produced using the method described in the EXAMPLE or a similarmethod.)

Dat:physicochemical properties wherein:

F:FAB-MS (M+H)+

FN:FAB-MS (M−H)−

E:EI-MS

M:melting point [° C.]

(dec.):Decomposition

N1:characteristic peaks δ ppm of NMR (DMSO-d6, TMS internal standard)

Ac:acetyl

Bn:benzyl

Ph:phenyl

Ts:4-toluenesulfonyl

Ms:methanesulfonyl

Me:methyl

Et:ethyl

Where two or more positions to permit substitution are present, theposition substituted is indicated as a prefix (e.g.,6-MeO-7-HOrepresents 6-methoxy-7-hydroxy.).

TABLE 1 Rco Rex Str DAT 1 1

F: 249 2 1

F: 277 3 2

F: 206 4 3

F: 327 5 3

F: 353 6 3

F: 341 7 3

F: 398 8 3

F: 381 9 3

F: 310 10  3

F: 341 11  4

F: 356 12  4

F: 375 13  5

F: 299 14  5

FN: 311 15  5

FN: 281 16  5

FN: 311

TABLE 2 Rco Rex Str DAT 17 5

FN: 326 18 5

F: 282 19 5

F: 311 20 5

FN: 326 21 6

F: 298 22 6

FN: 279 23 6

FN: 325 24 6

F: 282 25 6

F: 310 26 6

F: 312 27 6

F: 312 28 6

FN: 325 29 7

F: 188 30 8

E: 279 31 8

E: 308 32 8

F: 264

TABLE 3 Rco Rex Str DAT 33 8

F: 309 34 8

F: 292 35 8

F: 263 36 8

F: 294 37 8

E: 293 38 9

F: 322 39 9

E: 321 40 3

F: 341 41 4

FN: 344 42 5

FN: 311 43 5

FN: 316 44 6

F: 312 45 6

F: 317 46 8

F: 293 47 8

FN: 297 48 9

F: 322 49 19 

F: 207

TABLE 4 Co Syn Str DAT Co Syn Str DAT 1 1

F: 378 2 1

E: 377 3 2

F: 593 4 2

N1: 4.15(4H, t, J=4.4Hz), 8.52(1H, s), 10.41(1H, s). 5 2

F: 593 6 2

F: 497 7 12

M: 206- 208 Z —

062) SPECS and BIOSPECS B.V. (Catalog No.: AE-848/ 3855062)

TABLE 5 (Ia)

Co Syn X Y NR²R³ R⁴ Sal DAT 8 3 N O

— M: 229-230; N1: 3.85 (4H, t, J = 4.8 Hz), 7.22-7.25 (1H, m), 10.47(1H, s) 9 3 N O

— M: 291-293; N1: 2.74 (3H, s), 7.39 (1H, t, J = 7.8 Hz), 8.23 (1H, s)10 4 N O

— M: 266-268; N1: 3.87 (4H, t, J = 4.8 Hz), 7.51 (1H, t, J = 7.8 Hz),10.78 (1H, s) 11 4 N O

— F: 487 12 5 N O

HCl N1: 3.87 (4H, t, J = 4.8 Hz), 8.87 (1H, s), 11.06 (1H, s) 13 5 N O

HCl N1: 3.88 (4H, t, J = 4.8 Hz), 9.34 (1H, s), 10.88 (1H, s) 14 5 N O

2HCl N1: 3.86 (4H, t, J = 4.8 Hz), 8.14 (1H, s), 10.85 (1H, s) 15 5 N O

2HCl N1: 3.87 (4H, t, J = 4.4 Hz), 7.56 (1H, t, J = 7.8 Hz), 11.26 (1H,s) 16 5 N O

HCl N1: 3.87 (4H, t, J = 4.4 Hz), 8.84 (1H, s), 10.72 (1H, s) 17 5 N O

2HCl M: 203-207; N1: 3.86 (4H, t, J = 4.9 Hz), 7.52 (1H, t, J = 7.8 Hz),10.71 (1H, s) 18 5 N O

— N1: 1.35-1.48 (1H, m), 3.85 (4H, t, J = 4.4 Hz), 10.19 (1H, s)

TABLE 6 Co Syn X Y NR²R³ R⁴ Sal DAT 19 5 N O

2HCl M: 203-206 20 5 N O

— F: 487 21 5 N O

2HCl M: 173-175; N1: 7.53 (1H, t, J = 7.8 Hz), 8.24-8.29 (2H, m), 11.01(1H, s) 22 5 N O

HCl N1: 3.87 (4H, m), 8.30 (2H, s), 10.06 (1H, s) 23 5 N O

2HCl N1: 4.39 (2H, s), 7.47 (1H, t, J = 7.7 Hz), 10.87 (1H, s) 24 6 N O

— N1: 2.09 (3H, s), 3.87 (4H, t, J = 4.9 Hz), 10.11 (1H, s) 25 7 N O

2HCl M: 213-217 26 7 N O

3HCl M: 203-205 27 7 N O

2HCl N1: 1.50-1.90 (5H, m), 3.86 (4H, t, J = 4.9 Hz), 11.00 (1H, s) 28 7N O

2HCl N1: 1.83-2.06 (4H, m), 3.86 (4H, t, J = 4.4 Hz), 10.37 (1H, s) 29 8N O

— N1: 2.84 (4H, s), 3.85 (4H, t, J = 4.9 Hz), 7.38-7.40 (1H, m) 30 9 N O

HCl M: 293-295 31 10  N O

2HCl M: 237-240

TABLE 7 Co Syn X Y NR²R³ R⁴ Sal DAT 32 10 N O

2HCl N1: 3.87 (4H, t, J = 4.4 Hz), 7.51-7.55 (2H, m), 10.68 (1H, s) 3310 N O

HCl M: 262-266; N1: 3.86 (4H, t, J = 4.4 Hz), 8.37 (2H, d, J = 8.8 Hz),8.70 (1H, dd, J = 1.5, 4.9 Hz) 34 11 N O NH₂ H — N1: 7.59 (1H, dd, J =4.8, 7.8 Hz), 7.72 (2H, br s), 8.45 (1H, s) 35 12 N O

— M: 237-239 36 12 N NH

— M: 248-250 37 12 N S

— M: 201-202 38 12 N O

H — M: 182-183 39 12 CH S

H HCl M: 202-205 40 13 N O

2HCl M: 237-240; N1: 3.09-3.14 (2H, m), 7.50 (1H, t, J = 7.8 Hz), 10.59(1H, s) 41 13 N O

3HCl M: 178 (dec.); N1: 3.13-3.16 (2H, m), 7.54 (1H, t, J = 7.8 Hz),11.04 (1H, s) 42 13 N O

2HCl M: 282-285; N1: 3.09 (3H, s), 7.51 (1H, t, J = 7.8 Hz), 10.79 (1H,s) 43 13 N O

2HCl M: 257-261; N1: 4.81 (2H, s), 7.33- 7.53 (6H, m), 10.76 (1H, s) 4414 N O

2HCl M: 234-237; N1: 3.32 (6H, s), 7.53 (1H, t, J = 7.8 Hz), 10.75 (1H,s) 45 15 N O

HCl M: 244-245; N1: 3.87 (4H, t, J = 4.9 Hz), 7.49-7.67 (5H, m), 10.47(1H, s)

TABLE 8 Co Syn X Y NR²R³ R⁴ Sal DAT 46 15 N O

2HCl N1: 3.87 (4H, t, J = 4.9 Hz), 7.53 (1H, t, J = 7.8 Hz), 10.73 (1H,s) 47 15 N O

2HCl N1: 3.87 (4H, t, J = 4.9 Hz), 7.55 (1H, t, J = 7.8 Hz), 10.86 (1H,s) 48 15 N O

HCl M: 195-197; N1: 3.62 (3H, s), 7.44 (1H, t, J = 7.8 Hz), 10.25 (1H,s) 49 16 N O

HCl M: 164-167; N1: 2.55-2.64 (4H, m), 7.43 (1H, t, J = 7.8 Hz), 10.17(1H, s) 50 17 N O

HCl M: 270-272; N1: 4.15 (4H, t, J = 4.8 Hz), 7.32 (1H, t, J = 7.8 Hz),8.70 (1H, dd, J = 1.9, 4.9 Hz) 51 17 N O

HCl M: 182-184; N1: 3.87 (3H, s), 7.45 (1H, t, J = 7.8 Hz), 8.69 (1H,dd, J = 1.5, 4.9 Hz) 52 17 N O

HCl M: 306 (dec.); N1: 3.85 (4H, t, J = 4.9 Hz), 6.91 (2H, d, J = 8.8Hz), 8.32 (2H, d, J = 8.8 Hz) 53 17 N O

HCl N1: 2.18 (3H, s), 8.11 (1H, s), 12.50 (1H, s) 54 18 N O

2HCl M: 186-190; N1: 4.15 (4H, t, J = 4.4 Hz), 4.59 (2H, t, J = 4.8 Hz),7.49 (1H, t, J = 7.8 Hz) 55 18 N O

2HCl M: 283-286; N1: 1.35-1.47 (1H, m), 4.56 (2H, t, J = 4.9 Hz), 7.49(1H, t, J = 7.8 Hz) 56 18 N O

2HCl M: 233-235; N1: 1.30 (6H, t, J = 7.3 Hz), 4.53 (2H, t, J = 4.9 Hz),7.49 (1H, t, J = 7.8 Hz) 57 18 N O

2HCl M: 275-277; N1: 3.19-3.28 (2H, m), 7.15 (2H, d, J = 8.8 Hz), 8.46(2H, d, J = 8.8 Hz)

TABLE 9 (Ia)

Co Syn R Sal DAT 58 47

HCl N1: 3.29-3.34 (2H, m), 7.46 (1H, t, J = 7.8 Hz), 8.68-8.71 (2H, m)59 48

2HCl M: 206-210; N1: 4.17 (4H, t, J = 4.9 Hz), 7.73 (1H, d, J = 7.8 Hz),7.81 (1H, s) 60 49 —NHCOCF₃ — N1: 3.86 (4H, t, J = 4.9 Hz), 7.64 (1H,dd, J = 5.0, 7.7 Hz), 11.43 (1H, s) 61 18

— N1: 7.56-7.67 (3H, m), 8.48-8.53 (2H, m), 8.62-8.65 (1H, m) 62 50

— N1: 3.83-3.88 (6H, m), 7.45 (1H, t, J = 7.9 Hz), 8.67-8.72 (2H, m) 6350

— N1: 1.85-2.07 (4H, m), 4.10-4.14 (6H, m), 8.65-8.70 (2H, m) 64 51

3HCl N1: 2.85 (3H, br s), 4.16 (4H, t, J = 4.4 Hz), 7.66 (1H, dd, J =4.9, 7.8 Hz) 65 18

— N1: 4.19 (2H, t, J = 4.9 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.96 (1H, s)66 51

2HCl M: 196-198; N1: 3.33 (6H, s), 7.50 (1H, t, J = 7.8 Hz), 8.07-8.11(2H, m) 67 51

HCl N1: 4.12 (4H, t, J = 4.3 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.65-8.69(2H, m) 68 51

2HCl M: 243-248; N1: 3.01-3.10 (2H, m), 3.15- 3.20 (2H, m), 7.65 (1H,dd, J = 4.9, 7.8 Hz) 69 52

3HCl M: 250-253; N1: 4.56 (2H, t, J = 4.9 Hz), 7.49 (1H, t, J = 7.8 Hz),8.10 (1H, d, J = 7.8 Hz) 70 53

2HCl N1: 3.05 (3H, s), 4.19 (4H, t, J = 4.4 Hz), 7.91 (1H, br s)

TABLE 10 Co Syn R Sal DAT 71 15

2HCl M: 244-245; N1: 1.84 (3H, s), 4.11-4.18 (6H, m), 7.64-7.72 (3H, m)72 51

2HCl M: 196-201; N1: 4.15 (4H, t, J = 4.4 Hz), 7.74 (1H, s), 9.34 (1H,s) 73 15

HCl N1: 5.79 (1H, d, J = 10.8 Hz), 6.30 (1H, d, J = 17.1 Hz), 10.40 (1H,s) 74 51

2HCl N1: 4.15 (4H, t, J = 4.9 Hz), 4.53-4.56 (2H, m), 8.05 (1H, s) 75 18

HCl N1: 1.24 (3H, t, J = 6.8 Hz), 4.22 (2H, q, J = 6.8 Hz), 4.89 (2H, s)76 16

HCl M: 264-267; N1: 4.79 (2H, s), 7.45 (1H, t, J = 7.8 Hz), 7.64 (1H,dd, J = 4.9, 7.8 Hz) 77 54

HCl M: 243-244; N1: 3.78 (2H, t, J = 4.9 Hz), 4.14 (4H, t, J = 4.9 Hz),7.98-7.99 (1H, m)

TABLE 11 (Ia)

Co Syn R⁴ Sal DAT 78 47

2HCl N1: 3.05-3.14 (2H, m), 3.26-3.31 (2H, m), 7.10 (2H, d, J = 8.8 Hz)79 55

— N1: 4.15 (4H, t, J = 4.9 Hz), 7.66 (1H, dd, J = 4.9, 7.8 Hz), 8.15(1H, dd, J = 1.5, 7.8 Hz) 80 12

— N1: 4.16 (4H, t, J = 4.9 Hz), 7.67 (1H, dd, J = 4.9, 7.3 Hz),8.34-8.35 (2H, m) 81 56

— M: 343-347; N1: 7.64 (1H, dd, J = 4.9, 7.3 Hz), 8.66-8.69 (2H, m),11.72 (1H, br)

TABLE 12 (Ia)

Co X Y R⁴ A1 N S

A2 N S

A3 N S

A4 N S

A5 N S

A6 N S

A7 N S

A8 N S

A9 N O

A10 N S

A11 N S

A12 N S

A13 N O

A14 N S

A15 N O

A16 N S

A17 N O

A18 N S

A19 N O

A20 N S

A21 N O

A22 N S

A23 N O

A24 N S

A25 N O

A26 N S

TABLE 13 Rco Rex Str DAT 50 10

F: 208 51 10

F: 240 52 11

E: 324 53 11

F: 321 54 11

F: 283 55 11

F: 253 56 11

F: 241 57 11

F: 321 58 11

F: 280 59 11

FN: 282 60 11

FN: 282 61 11

F: 297 62 11

FN: 227 63 11

F: 297 64 11

F: 329 65 11

F: 290 66 11

F: 329 67 12

F: 259 68 12

F: 313 69 12

F: 279

TABLE 14 Rco Rex Str DAT 70 12

F: 271 71 12

F: 254 72 13

F: 255 73 13

F: 293 74 14

F: 407 75 14

F: 317 76 14

F: 393 77 15

F: 299 78 15

F: 281 79 15

F: 397 80 15

F: 287 81 15

F: 321 82 15

F: 282 83 16

FN: 324 84 16

F: 271 85 16

F: 371 86 16

F: 339 87 16

FN: 369 88 16

F: 332 89 16

F: 339

TABLE 15 Rco Rex Str DAT 90 16

F: 326 91 16

F: 400 92 17

F: 339 93 17

F: 341 94 17

F: 369 95 18

FN: 359 96  3

F: 286 97  3

F: 287 98  3

F: 287 99  3

F: 292 100  3

F: 302 101   3

F: 422 102   8

F: 254 103   8

F: 254 104   8

F: 382 105   8

F: 269 106   9

F: 281 107   9

F: 283 108   9

F: 282 109   9

F: 282

TABLE 16 Rco Rex Str DAT 110  9

F: 299 111  9

F: 410 112  9

F: 286 113  9

F: 282 114  9

F: 282 115 11

F: 286 116 20

F: 254 117 21

F: 272 118 21

F: 272 119 22

F: 329 120 22

F: 400 121 23

F: 311 122 24

F: 259 123 24

F: 255 124 24

F: 269

TABLE 17 (Ib)

Co Syn X R¹ NR²R³ R⁴ Sal DAT 82 19 N H

— M: 111-112; N2: 3.86 (4H, m), 3.95 (4H, m), 8.56 (2H, m) 83 19 N 6-F

— M: 157-159; N2: 3.80 (4H, t, J = 4.7Hz), 3.94 (4H, t, J = 4.7Hz),8.50- 8.54 (2H, m) 84 19 N 6-MeO- 7-MeO

— M: 182-186 85 19 N 6-NO₂

— M: 238-240; N1: 3.83 (4H, t, J = 4.9Hz), 7.99 (1H, d, J = 8.8Hz), 8.82(1H, d, J = 2.4Hz) 86 19 N 6-AcHN

— M: 121-124 87 19 N 6-MeO

— M: 145-146; N1: 3.79 (4H, m), 3.87 (4H, m), 3.94 (3H, s) 88 19 N6-AcHN

— N1: 8.52 (1H, s), 8.86 (1H, m), 10.36 (1H, s) 89 19 N 6-MeO

— M: 161-163 89 19 N 6-MeO

— M: 218-220 90 19 N 6-MsHN

— N1: 3.10 (3H, s), 3.80-3.90 (8H, m), 10.18 (1H, br) 91 19 CH 6-MeO

— N1: 3.92 (8H, m), 7.96 (1H, d, J = 8.8 Hz), 8.22 (2H, m) 92 20 N6-MeO- 7-OH

— M: 202-204; N1: 3.70 (4H, t, J = 4.4Hz), 3.98 (3H, s), 7.07 (1H, s) 9320 N 6-HO

— M: 203-205; N1: 3.79 (4H, m), 3.87 (4H, m), 10.22 (1H, s) 94 20 N 6-HO

— M: 222-225 (dec.); N1: 3.72 (4H, m), 4.82 (1H, brs), 8.01 (1H, brs)

TABLE 18 Co Syn X R¹ NR²R³ R⁴ Sal DAT 96 20 N 6-HO

— M: 296—305 (dec.) 97 21 N 6-H₂N

— M: 184-186 98 22 N 6-OHCHN—

— M: 218-222; N1: 379 (4H, t, J = 4.2 Hz), 8.41 (1H, d, J = 1.5 Hz),10.59 (1H, s) 99 23 N 6-HO

— M: 243-249, N1: 4.07 (2H, s), 7.67 (1H, d, J = 8.8 Hz) 10.00 (1H, s)100 23 N 6-HO

— M: 258-262 (dec.) 101 23 N 6-HO

H — M: 259-260; N1: 3.57 (4H, t, J = 4.7 Hz), 8.55 (1H, s) 10.12 (1H, s)102 23 N 6-HO

— M: 249-250; N1: 3.82 (1H, m) 7.77 (1H, d, J = 9.6 Hz), 10.08 (1H, s)103 23 N 6-HO

— M: 221-225; N1: 1.20 (6H, d, J = 6.4 Hz). 7.80 (1H, d, J = 8.8 Hz)10.12 (1H, s) 104 23 N 6-HO

— M: 139-141 105 24 N 6-AcMeN—

— M: 204-206 106 25 N 6-TsHN—

— M: 199-200; N1: 2.32 (3H, s) 3.62 (4H, t, J = 4 Hz), 10.65 (1H, s) 10726 N 6-Me₂N—

— M: 124—125 108 27 N 6-HO

0.5 HCl M: 268-281 109 28 N 6-HO

Me — M: 281-284

TABLE 19 Co Ex. X R¹ NR²R³ R⁴ Sal DAT 110 29 N 7-HO

— M: 245-246 111 29 N 6-HO

— M: 266-269; N1: 3.74(4H, t, J=4.4Hz), 8.66(2H, d, J=9.1 Hz), 10.29(1H,s) 112 29 N 6-HO

— M: 226-227 113 29 N 6-HO

— N1: 1.94(2H, m), 2.69(1H, m), 7.65(1H, d, J=8.8Hz) 114 29 N 6-HO

— M: 275-277; N1: 7.83(1H, d, J=8.8Hz), 9.58(1H, d, J=1.5Hz), 10.09(1H,brs) 115 29 N 6-HO

— M: 280(dec.) 116 29 N 6-HO

— M: 239-241 117 29 N 6-HO

— M: 184-186; N1: 3.92(3H, s), 9.03(1H, br), 10.19(1H, s) 118 29 N 6-HO

— M: 280-284; N1: 3.68(4H, t, J=4.5Hz), 9.49(1H, s), 10.12(1H, s) 119 29N 6-HO

— M: 306-311(dec.); N1: 7.75(1H, d, J=8.8Hz), 9.29(2H, s), 10.10(1H, s)120 29 N 6-HO

— M: 254-255 121 29 N 6-HO

— M: 288-290¹ 122 29 N 6-HO

— M: 188-190; N1: 3.80(3H, s), 13.83(3H, s), 10.06(1H, s) 123 29 N 6-HO

— M: 224-227

TABLE 20 Co Syn X R¹ NR²R³ R⁴ Sal DAT 124 29 N 6-HO

— M: 285-288; N1: 3.88 (3H, s), 9.37 (1H, s), 10.03 (1H, s) 125 29 N6-HO

— M: 310-313; N1: 3.71 (4H, m), 3.87 (4H, m), 10.23 (1H, s) 126 29 N6-HO

— M: 178-180 127 30 N 6-HO

— M: 260-263; N1: 3.64 (4H, m), 3.86 (4H, m), 1H, 10.12 (1H, s) 128 30 N6-HO

— M: 280-282 129 31 N 6-HO

— M: 285 (dec.); N1: 3.62 (4H, t, J = 4.7 Hz), 5.51 (2H, br), 9.95 (1H,s) 130 32 N 6-HO

— M: 305 (dec.) 131 33 N 6-HO

— M: 306-309; N1: 3.71 (4H, t, J = 4.9 Hz), 10.18 (1H, s), 13.08 (1H, s)132 33 N 6-HO

— M: 204-206; N1: 4.78 (2H, d, J = 5.9 Hz), 5.28 (1H, t, J = 5.9 Hz),10.13 (1H, s) 133 34 N 6-HO

— M: 274-277; N1: 5.17 (2H, brs), 6.66 (1H, m), 10.08 (1H, s) 134 34 N6-MsHN

— N1: 3.07 (3H, s), 3.72-3.77 (4H, m), 10.07 (1H, br s) 135 35 N 6-HO

— M: 266-267 136 36 N 6-HO

— M: 261-264; N1: 8.10 (1H, br), 8.91 (1H, t, J = 1.4), 10.17 (1H, s)137 36 N 6-HO

— M: 306-309 138 37 N 6-HO

— M: 245-248

TABLE 21 Co Syn X R¹ NR²R³ R⁴ Sal DAT 139 38 N 6-HO

— M: 296-299; N1: 2.08 (3H, s), 10.08 (1H, s), 10.11 (1H, s) 140 39 N6-HO

— M: 152-157 141 40 N 6-HO

— M: 225-228; N1: 8.21 (1H, m), 10.16 (1H, brs), 10.44 (1H, brs) 142 40N 6-HO

— M: 206-207; N1: 8.33 (1H, s), 10.12 (1H, s), 10.18 (1H, s) 143 40 N6-HO

— M: 172-174 144 40 N 6-AcHN

— M: 145-150; N1: 8.48 (1H, d, J = 2.0 Hz), 10.33 (1H, brs), 10.44 (1H,brs) 145 40 N 6-MsHN

— M: 234-236; N1: 3.08 (3H, s), 3.74-3.79 (4H, m), 10.30 (2H, br) 146 40N 6-AcHN

— M: 145-148; N1: 2.12 (3H, s), 10.34 (1H, s), 10.56 (1H, s) 147 40 N6-AcHN

— M: 290 (d); N1: 2.12 (3H, s), 10.32 (1H, s), 10.83 (1H, s) 148 41 N6-HO

— M: 167-169 149 42 N 6-HO

— M: 144-147 150 43 N 6-HO

— M: 175-178; N1: 3.71-3.73 (4H, m), 10.17 (1H, s), 10.68 (1H, s) 151 43N 6-HO

— M: 239-243; N1: 2.33-2.42 (1H, m), 3.66-3.69 (4H, m), 9.96 (1H, s)

TABLE 22 Co Ex. X R¹ NR²R³ R⁴ Sal DAT 152 43 N 6-HO

— M: 214-216; N1: 3.68-3.70 (6H, m), 10.14 (1H, s), 10.34 (1H, s) 153 43N 6-HO

— M: 246-247 154 43 N 6-HO

— M: 251-252 155 43 N 6-HO

— N1: 3.86 (3H, s), 10.14 (1H, s), 10.26 (1H, s) 156 43 N 6-HO

— M: 182-183 157 43 N 6-HO

— N1: 3.72-3.74 (4H, m), 9.70- 9.99 (1H, br), 10.45 (1H, br s) 158 43 N6-HO

— M: 232-233 159 44 N

— M: 182-183 160 45 N

— M: 224-227 161 45 N

— M: 199-202; N1: 8.76 (1H, d, J = 2.4 Hz), 8.49 (2H, m), 10.74 (1H,brs) 162 46 CH 6-HO

— M: 250-253

TABLE 23 (Ib)

Co Syn B R Sal DAT 163 17

OMe 2HCl N1: 3.84 (4H, t, J = 4.9 Hz), 3.89 (3H, s), 9.55 (1H, s) 164 17

OH HCl M: 261-266; N1: 3.84 (4H, t, J = 4.9 Hz), 7.91 (1H, s), 9.53 (1H,s) 165 18

3HCl M: 167-170; N1: 3.61 (2H, br s), 4.61 (2H, t, J = 4.9 Hz), 9.54(1H, s) 166 47

3HCl N1: 3.26-3.31 (2H, m), 7.54 (1H, t, J = 7.8 Hz), 9.53 (1H, s) 16717

NO₂ HCl M: 272-273; N1: 4.20 (4H, t, J = 4.9 Hz), 7.97(1H, d, J = 6.4Hz), 9.52 (1H, s) 168 34

NH₂ 2HCl M: 195-200; N1: 4.25 (4H, t, J = 4.9 Hz), 7.64 (1H, t, J = 7.8Hz), 9.55 (1H, s) 169 57

NHAc HCl N1: 2.10 (3H, s), 9.52 (1H, s), 10.32 (1H, s) 170  3

NHSO₂Ph HCl N1: 8.75 (1H, d, J = 6.4 Hz), 9.49 (1H, s), 10.62 (1H, s)171  2

2HCl M: 200-203; N1: 8.89-8.90 (1H, m), 9.53 (1H, s), 10.84 (1H, s) 17217

OH HCl M: 233-238; N1: 4.73 (4H, br), 7.43 (1H, t, J = 7.8 Hz), 10.02(1H, br) 173 18

2HCl M: 201-206; N1: 3.19-3.29 (2H, m), 7.55 (1H, t, J = 7.8 Hz), 8.50(1H, br) 174 17

OH HCl M: 269-274; N1: 7.39 (1H, t, J = 7.8 Hz), 8.06 (1H, d, J = 5.9Hz), 9.44 (1H, s) 175 18

2HCl N1: 3.20-3.29 (2H, m), 4.60 (2H, t, J = 4.9 Hz), 9.50 (1H, s)

TABLE 24 Co Syn B R Sal DAT 176 17

OMe HCl M: 159-162; N1: 3.89(3H, s), 7.55(1H, t, J=7.8Hz), 8.02(1H, d,J=7.8Hz) 177 17

OH HCl M: 274-279; N1: 4.22(4H, t, J=4.9Hz), 7.41(1H, t, J=7.8Hz),10.05(1H, br) 178 18

2HCl N1: 4.59(2H, t, J=4.9Hz), 7.57(1H, t, J=7.8Hz), 7.68(1H, dd, J=4.9,8.3Hz) 179 17

OH HCl M: 235-237; N1: 4.19(4H, br s), 7.43(1H, t, J=7.8Hz),8.27-8.34(1H, m) 180 18

2HCl N1: 4.19(4H, br s), 8.28(1H, br s), 8.57(1H, br) 181 17

NO₂ HCl N1: 3.78-3.79(4H, m), 7.83-7.89(3H, m), 8.88(1H, d, J=7.8Hz) 18234

NH₂ 2HCl N1: 4.11(4H, br s), 7.47(1H, d, J=7.8Hz), 7.62(1H, t, J=7.8Hz)183 57

NHAc HCl N1: 2.10(3H, s), 7.52(1H, t, J=7.8Hz), 10.25(1H, s) 184 3

NHSO₂Ph HCl N1: 4.10(4H, br s), 8.17-8.28(3H, m), 10.83(1H, s) 185 2

2HCl M: 196-201; N1: 4.15(4H, br s), 8.85-8.87(2H, m), 10.97(1H, s) 18617

OH HCl M: 252-258; N1: 3.95(3H, s), 4.23(4H, br s), 10.04(1H, br) 187 18

2HCl N1: 4.67(2H, t, J=4.9Hz), 8.12(1H, d, J=7.8Hz), 8.49(1H, br) 188 17

2HCl M: 266.267; N1: 4.60-4.63(2H, m), 8.16(1H, s), 10.68(1H, br) 189 17

OH HCl M: 214-220; N1: 4.26(4H, br), 7.45(1H, t, J=7.8Hz), 7.82(1H, s)190 17

OH HCl M: 207-210; N1: 7.40(1H, t, J=7.8Hz), 7.86(1H, d, J=7.8Hz),8.51(1H, d, J=5.3Hz) 191 17

OH HCl M: 262-268(d); N1: 4.58(4H, br), 8.87(1H, d, J=2.0Hz), 9.09(1H,d, J=2.0Hz) 192 58

OH 2HCl M: 270-273; N1: 4.66-4.68(2H, m), 7.55(1H, br s), 10.05(1H, br)

TABLE 25 (Ib)

Co R⁴ Co R⁴ Co R⁴ B1

B2

B3

B4

B5

B6

TABLE 26 (Ib)

Co B R Co B R Co B R B7

CO₂NHMe B8

OH B9

OH B10

CH₂OH B11

CH₂OH B12

CH₂OH B13

CONH₂ B14

CONH₂ B15

CONH₂ B16

OH B17

OH B18

OH B19

CH₂OH B20

CH₂OH B21

CH₂OH B22

CONH₂ B23

CONH₂ B24

CONH₂ B25

OH B26

OH B27

OH B28

CH₂OH B29

CH₂OH B30

CH₂OH B31

CONH₂ B32

CONH₂ B33

CONH₂

Production methods of the starting compounds shown in the foregoingtables are explained in the following Reference Examples.

Reference Example 1

A suspension of 2-chloro-3-cyanopyridine, ethyl glycolate and sodiumcarbonate in 3-methyl-1-butanol was refluxed for 3 days. The solvent wasevaporated and water was added to the residue to crystallize to giveReference Example Compound (hereinbelow, abbreviated as Rco) 1.

Reference Example 2

A suspension of 2-chloro-3-cyanopyridine, glycine ethyl esterhydrochloride and sodium carbonate in 3-methyl-1-butanol was refluxedfor 6 days. The solvent was evaporated. After the obtained residue wasdiluted with ethyl acetate and water, insoluble solids were filteredoff. The separated organic layer was concentrated under reducedpressure. The residue was dissolved in ethanol, sodium ethoxide wasadded, and the mixture was stirred at room temperature for 15 minutes.The reaction solution was concentrated, and ethyl acetate saturatedaqueous sodium hydrogencarbonate were added. The separated organic layerwas concentrated under reduced pressure and the residue was purifiedwith silica gel column chromatography to give Rco 3.

Reference Example 3

Dimethylaminopyridine and benzoyl chloride were added to a solution of3-aminothieno[2,3-b]pyridine-2-carboxylic acid ethyl ester in pyridine.The reaction mixture was stirred at room temperature for 18 hours, andconcentrated. 1M Hydrochloric acid was added, and the mixture wasextracted with chloroform. The organic layer was concentrated underreduced pressure. The obtained residue was purified with silica gelcolumn chromatography to give Rco 4.

Reference Example 4

Phosphorous oxychloride was added to a solution of Rco 49 and4-nitrobenzoic acid and the reaction mixture was stirred at −15C for 15minutes. Ice and water was added to this reaction mixture. Theprecipitated crystals were collected to give Rco 11.

Reference Example 5

1M Sodium hydroxide was added to a solution of Rco 4 in methanol. Thereaction mixture was stirred at room temperature for 2 hours, and 1Mhydrochloric acid was added. The precipitated crystals were collected togive Rco 13.

Reference Example 6

Thionyl chloride was added to Rco 13. The mixture was refluxed for 2hours, cooled to room temperature and then concentrated. DMF and aqueousammonia were added to the obtained residue and the reaction mixture wasstirred at room temperature for 2 hours. Water was added to theresulting mixture and extracted with chloroform. The organic layer wasconcentrated under reduced pressure to give Rco 21.

Reference Example 7

Formamide was added to Rco 1 and the mixture was stirred at 200C for 2hours. After the mixture was cooled to room temperature, theprecipitated crystals were collected to give Rco 29.

Reference Example 8

2M potassium hydroxide was added to a solution of Rco 21 in methanol andthe mixture was stirred at 100C for 1 hour. After being cooled to roomtemperature, hydrochloric acid was added. The precipitated crystals werecollected to give Rco 30.

Reference Example 9

Acetic acid and 48% hydrobromic acid were added to Rco 36 and themixture was refluxed for 17 hours. After the reaction solution wasconcentrated under reduced pressure, diethyl ether was added and thereaction mixture was concentrated under reduced pressure. Sodium acetateand acetic anhydride were added to the obtained residue, and the mixturewas stirred at 110C for 2 hours. Ice and then water were added to thisreaction mixture under ice cooling. The precipitated crystalswerecollected to give Rco 38.

Reference Example 10

Ethanol was added to a solution of 3-cyanobenzoic acid methyl ester inchloroform and gaseous hydrogen chloride was passed into the mixture at0C for 15 minutes. Further, the solution was sealed and the solution wasstirred at 0C for 17 hours. The reaction mixture was concentrated, etherwas added, and the precipitated crystals were collected to give Rco 50.

Reference Example 11

2-Propanol was added to a mixture of 5-acetoamidoanthranilic acid,3-nitrobenzimidic acid ethyl ester hydrochloride and sodium methoxide,and the mixture was refluxed for 3 days. The reaction solution wasallowed to cool to room temperature. The obtained solid was collected togive Rco 52.

Reference Example 12

A solution of cyclohexanecarbonyl chloride in benzene was added indropwise to a solution of 2-amino-5-methoxybenzamide anddimethylaminopyridine in pyridine at room temperature, and the mixturewas stirred for 2 hours. The reaction mixture was concentrated, and theresidue was dissolved with ethyl acetate. After the organic layer waswashed with 1M hydrochloric acid and saturated aqueous sodiumhydrogencarbonate, it was concentrated and the obtained residue wasdissolved with methanol. 2M Sodium hydroxide was added. After thereaction solution was refluxed for 2 hours, it was neutralized with 12Mhydrochloric acid. The solvent was evaporated and the crystals werefiltered to give Rco 67.

Reference Example 13

THF and DMF were added to a mixture of 2-amino-5-methoxybenzamide, EDCIhydrochloride, HOBt and pyrazinecarboxylic acid, and the mixture wasstirred at room temperature for 3 days. The solvents were evaporated,and the crystals were collected and dissolved in methanol and 2M sodiumhydroxide. The reaction solution was refluxed for 3 hours andneutralized with 12M hydrochloric acid. The obtained crystals werecollected to give Rco 72.

Reference Example 14

Dimethylaminopyridine, TEA, ethanol and tosyl chloride were added to asuspension of Rco 55 in chloroform, and the reaction mixture was stirredat room temperature for 12 hours. DMSO was added to it to give asolution. Then, the reaction solution was stirred for 12 hours. Again,dimethylaminopyridine, TEA and tosyl chloride were added and thereaction solution was stirred for 18 hours. The reaction solution wasconcentrated, and the residue was diluted with ethyl acetate andpurified according to a conventional method to give Rco 74.

Reference Example 15

48% Hydrobromic acid was added to a solution of Rco 70 in acetic acid,and the mixture was refluxed for 2 days. After the reaction solution wasallowed to cool, it was concentrated, and sodium acetate and aceticanhydride were added to the obtained residue. The reaction solution wasrefluxed for 3 hours. After the reaction solution was allowed to cool,it was concentrated and ether was added to the solution, followed bycollection of crystals to give Rco 77.

Reference Example 16

Sodium acetate and acetic anhydride were added to Rco 60, and themixture was refluxed for 40 minutes. After the reaction mixture wasallowed to cool, the precipitated crystals were collected to give Rco83.

Reference Example 17

Sodium methoxide was added to a solution of 3-hydroxybenzimidate ethylester hydrochloride and 5-hydroxyanthranilic acid in methanol, and themixture was refluxed for 30 minutes. After the reaction solution wascooled to room temperature, the precipitate was collected. Sodiumacetate and acetate anhydride were added to the obtained precipitate andthe mixture was refluxed for 30 minutes. After the reaction solution wasallowed to cool, the precipitated crystals were collected to give Rco92.

Reference Example 18

Concentrated hydrochloric acid was added to Rco 52, and the mixture wasstirred at 80C. The reaction mixture was allowed to cool, filtered, andconcentrated under reduced pressure to give6-amino-2-(3-nitrophenyl)-3H-quinazoline-4-one hydrochloride. After theobtained compound was neutralized, pyridine, dimethylaminopyridine andmethanesulfonyl chloride were added. The reaction solution was stirredat room temperature for 20 hours, the solvent was evaporated and thecrystals were collected to give Rco 95.

Reference Example 19

1,8-diazabicyclo[5,4,0]-7-undecene (DBU) was added to a solution of2-chloro-3-cyanopyridine and ethyl glycolate in ethanol and the reactionmixture was refluxed for 21 hours. The resulting mixture was evaporatedunder reduced pressure, diluted with ethyl acetate and then, washed withwater and brine. The organic layer was concentrated under reducedpressure and crystallized to give Rco 49.

Reference Example 20

Aqueous ammonia was added to a solution of Rco 96 in methanol, and thereaction solution was stirred at room temperature for 3 hours. Methanolin the reaction mixture was evaporated under reduced pressure and thecrystals were collected to give Rco 116.

Reference Example 21

Aqueous ammonia was added to a solution of Rco 98 in methanol, and thereaction solution was stirred at room temperature overnight. Methanol inthe reaction mixture was evaporated under reduced pressure and thecrystals were collected to give Rco 117.

Reference Example 22

EDCI hydrochloride and HOBt were added to a solution of 3-acetoxybenzoicacid in DMF, and the reaction mixture was stirred at room temperaturefor 10 minutes. Then, 2-amino-5-methoxybenzamide was added, and thereaction mixture was stirred at room temperature for 1 hour. The solventwas evaporated under reduced pressure, and waster and THF were added.After the extraction with ethyl acetate, the organic layer was washedwith brine, evaporated under reduced pressure, and crystallized to giveRco 119.

Reference Example 23

Acetic anhydride was added to Rco 105 and sodium acetate, and thereaction mixture was stirred at 110C for 1 hour and 15 minutes. Undercooling, the precipitated crystals were collected to give Rco 121.

Reference Example 24

Aqueous ammonia was added to a solution of Rco 99 in dioxane, and thereaction mixture was stirred at room temperature for 13 days. Thesolvent was evaporated under reduced pressure and the crystals werecollected to give a mixture of amido3-(3-methoxybenzoylamino)thiophene-2-carboxylate and Rco 122. 2M aqueoussodium hydroxide was added to a solution of this mixture in 2-propanoland the reaction solution was refluxed for 21 hours. After being cooled,it was neutralized and the precipitated crystals were collected to giveRco 122.

Example 1

Phosphorous oxychloride was added to Rco 33 and the mixture was refluxedfor 20 minutes. The reaction mixture was concentrated under reducedpressure, and was azeotropically concentrated with toluene. Morpholinewas added to the obtained residue and the mixture was refluxed for 10minutes. The reaction solution was concentrated under reduced pressureand the obtained crystals were washed with chloroform and water to giveCompound (hereinafter, abbreviated as Co) 1.

Example 2

1-Benzyl piperidine-1,2-dicarboxylate, HOBt and EDCI hydrochloride wereadded to a solution of a free form of Co 31 in DMF, and the mixture wasstirred at room temperature for 7 hour. The solvent was evaporated underreduced pressure. After being diluted with ethyl acetate, the organiclayer was washed with saturated aqueous sodium hydrogencarbonate andbrine. After the solution was dried over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure. The obtained residue waspurified with silica gel column chromatography and crystallized to giveCo 3.

Example 3

Benzenesulfonyl chloride (6.02 ml) was added to a solution of a freeform of C 31 (13.6 g) in pyridine (480 ml) at 0C and the mixture wasstirred at room temperature for 1.5 hours. The solvent was evaporatedunder reduced pressure. The obtained residue was dissolved in ethylacetate and the solution was washed with saturated aqueous sodiumhydrogencarbonate and brine. After the solution was dried over anhydroussodium sulfate, the solvent was evaporated under reduced pressure. Theobtained residue was purified with silica gel column chromatography(eluent; chloroform:methanol=96:4) and recrystallized (ethanol) to giveCo 8 (15.6 g).

Example 4

Picolinoyl chloride hydrochloride (9.40 g) and TEA (14.7 ml) were addedto a solution of a free form of Co 31 (15.3 g) in THF (1L) at 0C and themixture was stirred at room temperature for 1.5 hours. Then, additionalpicolinoyl chloride hydrochloride (4.00 g) was added and the mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure. After dissolving in ethyl acetate,the solution was washed with saturated aqueous sodium hydrogencarbonateand brine. After being dried over anhydrous sodium sulfate, the solventwas evaporated under reduced pressure and the obtained residue waspurified with silica gel column chromatography(chloroform:methanol=96:4) and recrystallized (ethanol) to give Co 10(15.4 g).

Example 5

3-Hydroxypicolinic acid (140 mg), EDCI hydrochloride (190 mg) and HOBt(135 mg) were added to a solution of a free form of Co 31 (300 mg) inDMF (20 ml) and the mixture was stirred at room temperature for 2 hours.The solvent was evaporated under reduced pressure. The obtained residuewas dissolved with ethyl acetate and THF. The solution was washed withwater and saturated aqueous sodium hydrogencarbonate. After the organiclayer was dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure. The obtained residue was purifiedwith silica gel column chromatography (chloroform:methanol=100:1). 4MHydrogen chloride/ethyl acetate was added to a solution of the obtainedresidue in chloroform and methanol. The solvent was evaporated underreduced pressure, and the obtained solid was crystallized from methanolto give Co 12 (207 mg).

Example 6

A suspension of a free form of Co 31 (300 mg), succinic anhydride (519mg) and acetic acid (1 ml) was stirred at 100C for 30 minutes. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified with silica gel column chromatography(chloroform:methanol=98:2) and recrystallized (methanol) to give Co 24(106 mg).

Example 7

To a solution of Co 18 (300 mg) in THF (12 ml) and ethanol (12 ml), 10%Pd—C (35 mg) was added, and the mixture was stirred at room temperatureunder hydrogen atmosphere (1 atm) for 4 hours. The reaction solution wasfiltered by Celite. After the filtrate was concentrated under reducedpressure, the obtained residue was purified with silica gel columnchromatography (chloroform:methanol=98:2−80:20) to give a free form ofCo 25 (178 mg). 1M Hydrochloric acid (1.00 ml) was added to a solutionof the obtained free form (153 mg) in THF (35 ml) and methanol (20 ml).The reaction solution was stirred at room temperature, then concentratedunder reduced pressure, and recrystallized (methanol) to givedihydrochloride of Co 25 (119 mg).

Example 8

A suspension of a free form of Co 31 (300 mg), succinic anhydride (519mg) and acetic acid (1 ml) was stirred at 100C for 30 minutes. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified with silica gel column chromatography(chloroform:methanol=98:2) and recrystallized (methanol) to give Co 29(57 mg).

Example 9

N-Carboethoxyphthalimide (262 mg) and TEA (0.166 ml) were added to asolution of a free form of Co 31 (346 mg) in THF (60 ml) and the mixturewas stirred at 80C for 1 day. After the reaction mixture was allowed tocool, water was added, and collected to give a free form of Co 30 (374mg). 1M Hydrochloric acid (1.55 ml) was added to a solution of theobtained free form (371 mg) in THF (200 ml) and the solution was stirredat room temperature. The precipitated crystals were collected to givehydrochloride of Co 30 (287 mg).

Example 10

Co 1 (22.4 g) and ammonium chloride (1.59 g) were suspended in a mixtureof ethanol (717 ml) and water (269 ml). Then, iron (33.2 g) was addedand the solution was refluxed for 9 hours. While the reaction solutionwas still hot, hot THF was added, and the mixture was filtered withCelite. After most of the solvent was evaporated under reduced pressure,the precipitate was collected, and washed with diethyl ether to give afree form of Co 31 (18.9 g). 1M Hydrochloric acid (0.870 ml) was addedto a solution of the obtained free form (101 mg) in THF (25 ml) and thesolution was stirred at room temperature. The precipitated crystals werecollected, and washed with methanol to give dihydrochloride of Co 31 (75mg).

Example 11

A solution of Rco 1 (1.03 g) in formamide (12 ml) was refluxed for 2hours. After the reaction mixture was cooled to room temperature, theobtained solids were collected to give Rco 29 (648 mg). Phosphorousoxychloride (7 ml) was added to a solution of obtained Rco 29 (630 mg)in pyridne (3.5 ml). The reaction mixture was refluxed for 2.5 hours.After being cooled to room temperature, the solvent was evaporated.Toluene (7 ml) was added to the obtained residue. After morpholine (7ml) was slowly added in dropwise under ice cooling, the reaction mixturewas refluxed for 3.5 hours. Further, THF (3 ml) and morpholine (20 ml)were added, and the reaction mixture was refluxed for 5 days, and thenconcentrated under reduced pressure. After the residue was diluted withethyl acetate, the crystals were collected, washed with ethyl acetate,saturated aqueous sodium hydrogencarbonate and water, and recrystallized(ethanol) to give Co 34 (372 mg).

Example 12

Phosphorous oxychloride (5 ml) was added to Rco 32 (396 mg) and themixture was refluxed for 50 minutes. The solvent was evaporated underreduced pressure. After morpholine (10 ml) was slowly added in dropwiseinto the obtained residue under ice cooling, the reaction mixture wasrefluxed for 30 minutes. The reaction mixture was concentrated underreduced pressure. The obtained crystals were washed with ethyl acetateand water, and recrystallized (ethanol) to give Co 35 (411 mg).

Example 13

Ethylenediamine (1.85 ml) was added to Co 11 (303 mg) and the mixturewas stirred at 90C for 2 hours. The solvent was evaporated under reducedpressure. The obtained residue was purified with silica gel columnchromatography (chloroform:methanol=80:20) and crystallized (methanol)to give a free form of Co 40 (269 mg). The obtained free form (266 mg)was subjected to salt formation as described in EXAMPLE 7, and theobtained residue was recrystallized (methanol) to give dihydrochlorideof Co 40 (153 mg).

Example 14

DMF (10 ml) was added to Co 11 (285 mg) and the solution was stirred at110C for 2 hours and at 80C for 27 hours. The solvent was evaporatedunder reduced pressure. The obtained residue was dissolved in ethylacetate and THF. The reaction solution was washed with aqueous sodiumhydrogencarbonate and brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified with silica gel column chromatography(chloroform:methanol=98:2) to give a free form of Co 44 (167 mg). 1MHydrochloric acid (0.283 ml) was added to a solution of the obtainedfree form (70 mg) in THF (5 ml) and methanol (10 ml), and the solutionwas stirred at room temperature. The precipitated crystals werecollected to give dihydrochloride of Co 44 (72 mg).

Example 15

Benzoyl chloride (0.118 ml) was added to a solution of a free form of Co31 (297 mg) in pyridine (20 ml) under ice cooling and the mixture wasstirred at room temperature for 20 minutes. The solvent was evaporatedunder reduced pressure. The obtained residue was dissolved in ethylacetate and THF. The reaction solution was washed with aqueous sodiumhydrogencarbonate and brine. After being dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure. The obtainedresidue was recrystallized (methanol) to give a free form of Co 45 (301mg). The obtained free form (287 mg) was subjected to salt formation asdescribed in EXAMPLE 7 to give hydrochloride crystals of Co 45 (249 mg).

Example 16

1M Sodium hydroxide (11 ml) was added in two portions to a solution of afree form of Co 48 (171 mg) in methanol (60 ml) and THF (30 ml), and themixture was stirred at room temperature for 2.5 hours. The reactionmixture was acidified with 1M hydrochloric acid, and the organic solventwas evaporated under reduced pressure. The precipitate was collected,and washed with water and diethyl ether. The obtained crystals wererecrystallized (methanol/diethyl ether) to give Co 49 (116 mg).

Example 17

Phosphorous oxychloride (5 ml) was added to Rco 38 (452 mg), and themixture was refluxed for 30 minutes. After the reaction solution wascooled to room temperature, it was concentrated under reduced pressure.After adding THF (5 ml) and then slowly adding morpholine (4 ml) indropwise to the obtained residue under ice cooling, the ice bath wasremoved and the solution was refluxed for 1 hour. After the reactionmixture was cooled to room temperature the solvent was evaporated underreduced pressure. The obtained solid was washed with water and diethylether and purified with silica gel column chromatography(chloroform:methanol=98:2) to give a free form of Co 50 (411 mg). Theobtained free form (183 mg) was subjected to salt formation as describedin EXAMPLE 7 and recrystallized (methanol) to give hydrochloride of Co50 (129 mg).

Example 18

4-(2-Chloroethyl)morpholine hydrochloride (1.53 g) and potassiumcarbonate (1.90 g) were added to a solution of a free form of Co 50 (956mg) in DMF (35 ml), and the mixture was stirred at 70C for 2.5 days.After the reaction solution was cooled to room temperature, the solventwas evaporated under reduced pressure. The obtained solid was washedwith water and diethyl ether and purified with silica gel columnchromatography (chloroform:methanol=98:2) and crystallized (methanol) togive a free form of Co 54 (1.16 g). 4M Hydrochloric acid/ethyl acetate(1.14 ml) was added to a solution of the obtained free form (1.05 g) inTHF (140 ml) and methanol (70 ml), and the solution was stirred at roomtemperature. The solvents were evaporated under reduced pressure, andthe material was recrystallized (methanol) to give dihydrochloridecrystals of Co 54 (1.18 g).

Example 19

Phosphorous oxychloride (5 ml) was added to2-phenyl-3H-quinazoline-4-one (450 mg), and the mixture was refluxed for3 hours. The reaction mixture was concentrated. Saturated aqueous sodiumhydrogencarbonate was added and extracted with ethyl acetate. After theorganic layer was dried over anhydrous magnesium sulfate, the solventwas evaporated under reduced pressure. The obtained colorless crystalswere dissolved in benzene (10 ml) and morpholine (325 mg) was added. Thereaction mixture was refluxed overnight. Insoluble materials werefiltered off and the filtrate was diluted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodiumhydrogencarbonate, dried over anhydrous magnesium sulfate, and thenconcentrated under reduced pressure. The obtained residue was purifiedwith column chromatography (hexane ethyl acetate=5:1) and recrystallized(hexane-benzene) to give Co 82 (136 mg).

Example 20

Sodium cyanide (132 mg) was added to a solution of Co 84 (190 mg) inDMSO (5 ml), and the mixture was stirred at 180C for 2 hours. After thereaction mixture was allowed to cool, water was added to it and themixture was extracted with ethyl acetate. After the organic layer waswashed with brine and dried over anhydrous sodium sulfate, the solventwas evaporated under reduced pressure. The obtained residue wasrecrystallized (hexane/ethyl acetate) to give Co 92 (40 mg).

Example 21

Iron (415 mg) was added to a solution of Co 85 (500 mg) in acetic acid(12 ml), and the mixture was stirred at 105C for 1 hour. After thereaction solution was allowed to cool, chloroform and 1M sodiumhydroxide were added. The solution was filtered with Celite and thefiltrate was extracted with chloroform. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. 1M Hydrochloric acid (10 ml) wasadded to the obtained residue and the mixture was stirred at 85C for 90minutes. After the mixture was allowed to cool, 1M sodium hydroxide wasadded and extracted with chloroform, and the organic layer was washedwith brine. After the solution was dried over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure. The obtained residuewas purified with silica gel column chromatography (eluent;chloroform:methanol=50:1), and recrystallized (chloroform/hexane) togive Co 97 (374 mg).

Example 22

Acetic anhydride (3 ml) was added to a solution of Co 97 (149 mg) informic acid (3 ml), and the mixture was stirred at room temperature for2 hours. Water was added and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumhydrogencarbonate and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified withsilica gel column chromatography (eluent; chloroform:methanol=50:1), andrecrystallized (chloroform/hexane) to give Co 98 (46 mg).

Example 23

Phosphorous oxychloride (3 ml) was added to Rco 74 (270 mg), and themixture was refluxed for 0.5 hours. The reaction mixture wasconcentrated under reduced pressure, and morpholine (10 ml) was added.After the reaction mixture was refluxed for 1 hour, the reaction mixturewas concentrated under reduced pressure and diluted with ethyl acetate.The organic layer was washed with saturated aqueous sodiumhydrogencarbonate, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. After purifying by silica gelcolumn chromatography (eluent; hexane:ethyl acetate=5:1), ethanol (2 ml)and 20% potassium hydroxide (100 mg) were added, and the mixture wasstirred at room temperature for 40 minutes. The reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withsaturated aqueous sodium hydrogenicarbonate, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedcrystals were washed with a mixture of ethyl acetate and hexane, andrecrystallized (ethyl acetate/hexane) to give Co 99 (30 mg).

Example 24

Sodium hydroxide (43 mg), potassium carbonate (37 mg) andtetra-n-butylammonium hydrogensulfate (2 mg) were added to a solution ofCo 86 (95 mg) in toluene (15 ml), and the mixture was stirred at 35C for0.5 hour, followed by addition of dimethylsulfate (34 mg) and stirringat 35C for 2 hours. The reaction solution was filtered and the filtratedwas concentrated under reduced pressure. The residue was purified withsilica gel column chromatography (eluent; chloroform:methanol=20:1), andrecrystallized (chloroform/hexane) to give Co 105 (62 mg).

Example 25

p-Toluenesulfonyl chloride (124 mg) and pyridine (1 ml) were added to asolution of Co 97 (200 mg) in chloroform (6 ml), and the mixture wasstirred at room temperature for 45 minutes. 1M Hydrochloric acid wasadded and extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium hydrogencarbonate and brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was recrystallized (chloroform/hexane) to give Co 106 (165 mg).

Example 26

35% Formalin (5 ml) and formic acid (5 ml) were added to Co 97 (250 mg),and the mixture was stirred at 100C for 90 minutes. After the mixturewas allowed to cool, 1M sodium hydroxide was added and the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified with silica gel columnchromatography (eluent; hexane:ethyl acetate=4:1), and recrystallized(chloroform/hexane) to give Co 107 (133 mg).

Example 27

Phosphorous oxychloride (50 ml) was added to Rco 76 (6.2 g), and themixture was refluxed for 1 hour. The reaction solution was concentratedunder reduced pressure and the residue was dissolved in chloroform. Thechloroform layer was washed twice with saturated aqueous sodiumhydrogencarbonate, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give 6.0 g of crystals. To 802 mgof the crystals, thiomorpholine (500 mg) and benzene (10 ml) were added.The reaction mixture was heated with stirring at 70C for 1 hour, andthen diluted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium hydrogencarbonate and brine, dried overanhydrous magnesium sulfate, concentrated under reduced pressure, andpurified with silica gel column chromatography (hexane:ethylacetate=5:1) to give p-toluenesulfonic acid 4-thiomorpholino2-phenylquinazoline-6-yl (828 mg). 802 mg of this compound was dissolvedin methanol (10 ml) and THF (10 ml). 20% Potassium hydroxide (1.0 g) wasadded to the solution and the mixture was stirred at 70C for 1 hour.Water and 1M hydrochloric acid was added to neutralize the solution.Then, the solution was extracted with ethyl acetate, and the organiclayer was washed with brine. After the solution was dried over anhydrousmagnesium sulfate, the solution was concentrated under reduced pressureand recrystallized (ethyl acetate-hexane) to give Co 108 (151 mg).

Example 28

Ammonium acetate (1.2 g) was added to acetic acid2-methyl-4-oxo-4H-benzo[d][1,3]oxazine-6-yl ester (3 g), and the mixturewas stirred at 150C for 30 minutes. After cooling to 80C, methanol wasadded to the mixture and the mixture was stirred at 80C for 1 hour.After the mixture was allowed to cool, the precipitated crystals werecollected and washed with methanol to give crystals (930 mg). To asolution of the obtained crystals (918 mg) in DMSO (10 ml)/chloroform (5ml), toluenesulfonyl chloride (1 ml), TEA (1 ml) and a catalytic amountof dimethylaminopyridine were added. The mixture was stirred at roomtemperature for 8 hours, and then extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium hydrogencarbonateand brine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. Phosphorous oxychloride (15 ml) wasadded to the obtained residue and the mixture was refluxed for 15 hours.After the reaction solution was allowed to cool, phosphorous oxychloridewas evaporated under reduced pressure. The residue was extracted withchloroform and washed with saturated aqueous sodium hydrogencarbonate.The organic layer was dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified withsilica gel column chromatography (eluent; chloroform:methanol=50:1) togive a liquid material (577 mg). To a solution of the obtained material(577 mg) in toluene (20 ml), morpholine (2 g) was added, and the mixturewas refluxed for 16 hours. The reaction solution was allowed to cool,and concentrated under reduced pressure. To a solution of the obtainedresidue in ethanol (15 ml), 20% potassium hydroxide (1 ml) was added,and the mixture was stirred at room temperature for 1 hour. The solventwas evaporated under reduced pressure. The residue was purified withsilica gel column chromatography (eluent; chloroform:methanol=20:1), andrecrystallized (chloroform/methanol/hexane) to give Co 109 (207 mg).

Example 29

Phosphorous oxychloride (10 mg) was added to Rco 78 (590 mg), and themixture was refluxed for 0.5 hours. The reaction mixture wasconcentrated, diluted with chloroform, and washed with saturated aqueoussodium hydrogencarbonate. The organic layer was dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. To theobtained colorless crystals, morpholine (10 ml) was added, and themixture was refluxed for 12 hours. The reaction mixture was diluted withchloroform, washed with water and saturated aqueous sodiumhydrogencarbonate, and dried over anhydrous magnesium sulfate. Theobtained organic layer was concentrated under reduce pressure. Theresidue was crystallized from chloroform-methanol, and furtherrecrystallized to give Co 110 (126 mg).

Example 30

Acetic acid (20 ml) and 48% hydrogen bromide (20 ml). were added to Rco67 (957 mg), and the mixture was stirred at an oil bath temperature of135C for 13 hours. After the mixture was allowed to cool to roomtemperature, precipitate was collected as a mixture of a startingmaterial and a desired compound. To the obtained solid, acetic anhydride(30 ml) and sodium acetate (112 mg) were added and the reaction mixturewas refluxed for 30 minutes. The reaction solution was allowed to cool,precipitate was collected. To the obtained solids, phosphorousoxychloride (10 ml) was added, and the mixture was refluxed for 30minutes and concentrated under reduced pressure. The obtained residuewas dissolved in chloroform and the solution was washed with saturatedaqueous sodium hydrogencarbonate. The organic layer was dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. Tothe obtained residue, morpholine (20 ml) was added and the mixture wasrefluxed for 15 hours. The reaction mixture was concentrated underreduced pressure and purified with silica gel column chromatography(eluent; chloroform methanol=50:1). The obtained crystals were washedwith a mixture of chloroform and ether to give Co 127 (193 mg).

Example 31

Iron (396 mg) was added to a solution of Co 111 (500 mg) in acetic acid(12 ml), and the mixture was stirred at 105C for 45 minutes. Thereaction solution was allowed to cool. Chloroform and 1M sodiumhydroxide were added to it. The mixture was filtered and extracted withchloroform. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified with silica gel column chromatography(eluent; chloroform:methanol=10:1) and recrystallized(chloroform/methanol/hexane) to give Co 129 (120 mg).

Example 32

1M Sodium hydroxide (8 ml) was added to a solution of Co 116 (564 mg) inethanol (8 ml) and THF (8 ml), and the reaction mixture was stirred atroom temperature for 15 hours. 1M Hydrochloric acid (8 ml) was added andthe solution was extracted with ether. The organic layer was washed withbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was recrystallized (methanol/ether/hexane)to give Co 130 (163 mg).

Example 33

Lithium aluminum hydride (67 mg) was added to a solution of Co 117 (325mg) in THF (40 ml), and the reaction mixture was stirred at 0C for 2hours. Water (0.1 ml), 1M sodium hydroxide (0.1 ml), and then water (0.3ml) were added and the mixture was stirred at room temperature for 30minutes. The mixture was dried over anhydrous sodium sulfate, filteredthrough silica gel, and concentrated under reduced pressure. The residuewas recrystallized (THF/hexane) to give Co 131 (158 mg).

Example 34

Co 112 (860 mg) was dissolved in a mixture of THF (30 ml), methanol (30ml) and ethanol (30 ml). 10% Pd—C (130 mg) was added and the reactionmixture was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 2 hours. Insoluble materials were removed by filtrationand the filtrate was concentrated to give 780 mg of solid. Of the solid,202 mg was recrystallized (ethanol/methanol) to give Co 133 (148 mg).

Example 35

Co 133 (202 mg) was dissolved in pyridine (10 ml). Methanesulfonylchloride (96 mg) was added to the reaction solution. The reactionmixture was stirred for 15 hours, and concentrated under reducedpressure. The obtained residue was dissolved in ethyl acetate. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The obtained crystalswere purified with column chromatography (chloroform-methanol=100:1) andrecrystallized (ethanol-ethyl acetate-hexane) to give Co 135.

Example 36

HOBt (75 mg) and EDCI hydrochloride (106 mg) were added to a solution ofCo 131 (177 mg) in DMF (12 ml), and the reaction solution was stirred at0C for 30 minutes and then at room temperature for 30 minutes. Aqueousammonia (2 ml) was added and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was extracted with chloroform, and theorganic layer was washed with water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified with silica gel column chromatography (eluent;chloroform:methanol=10:1) and recrystallized(chloroform/methanol/hexane) to give Co 136 (39 mg).

Example 37

Phosphorous oxychloride (15 ml) was added to Rco 87 (1.1 g), and themixture was refluxed for 1 hour. The reaction mixture was allowed tocool, and concentrated under reduced pressure. The mixture was dilutedwith chloroform and the organic layer was washed with saturated aqueoussodium hydrogencarbonate, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. To a solution of the obtainedresidue in toluene (40 ml), morpholine (5 g) was added and the reactionsolution was refluxed for 17 hours, allowed to cool, and concentratedunder reduced pressure. The residue was purified with silica gel columnchromatography (eluent; chloroform:methanol=30:1), and recrystallized(chloroform/ether/hexane) to give Co 138 (869 mg).

Example 38

Acetic anhydride (0.75 ml) and pyridine (1 ml) were added to a solutionof Co 129 (457 mg) in DMF (10 ml), and the reaction mixture was stirredat room temperature for 1 hour. 1M Sodium hydroxide (15 ml) and waterwere added and the reaction mixture was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified with silica gel columnchromatography (eluent; chloroform:methanol=10:1), recrystallized(chloroform/methanol/hexane), and washed with ether to give Co 139 (358mg).

Example 39

Benzene (10 ml), benzaldehyde (249 mg) and THF (10 ml) were added to Co133 (476 mg). The reaction mixture was azeotropically refluxed for 2hours and concentrated under reduced pressure, and the obtained residuewas dissolved in methanol (20 ml). Under ice cooling, sodium borohydride(50 mg) was added. The reaction mixture was stirred at room temperaturefor 1 hour, and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate, and the organic layer was washed with waterand brine, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified with silica gel columnchromatography (chloroform:methanol=100:1), and recrystallized (ethylacetate/hexane) to give Co 140 (259 mg).

Example 40

Co 133 (3.0 g) was dissolved in pyridine (50 ml). Benzenesulfonylchloride (1.9 g) was added to the mixture at room temperature. Afterstirring the mixture for 2 hours, the solvent was evaporated underreduced pressure. Ethyl acetate and water were added to the obtainedresidue and then the organic layer was washed with brine three times.The obtained organic layer was dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The obtained solid was purifiedwith silica gel column chromatography (chloroform:methanol=100:1) andrecrystallized (ethanol) to give Co 141 (3.0 g).

Example 41

THF (15 ml) and phenyl isocyanate (207 mg) were added to Co 133 (540mg). After the mixture was refluxed for 3 hours, phenyl isocyanate (500mg) was again added. The mixture was then refluxed for 4 hours. 1MSodium hydroxide (5 ml) was added. After the mixture was stirred for 15minutes, 1M hydrochloric acid (5 ml) was added to neutralize it. Thereaction mixture was extracted with chloroform, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified with silica gel column chromatography(chloroform:methanol=50:1) and recrystallized (2-propanol/diethylether/hexane) to give Co 148 (180 mg).

Example 42

THF (15 ml) and TEA (520 mg) were added to Co 133 (440 mg). Phenylchloroformate (498 mg) was added in dropwise to the reaction solution atroom temperature, and stirred at room temperature for 2 hours. Afteradding methanol, 1M sodium hydroxide (5 ml) was added under ice coolingand the reaction mixture was stirred for 20 minutes. 1M Hydrochloricacid (5 ml) was added to neutralize it. The reaction mixture wasextracted with chloroform, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedwith silica gel column chromatography (chloroform:methanol=50:1) andrecrystallized (ethyl acetate) to give Co 149 (189 mg).

Example 43

Isonicotinoyl chloride hydrochloride (280 mg) and pyridine (0.127 ml)were added to a solution of Co 133 (253 mg) in THF (10 ml), and thereaction mixture was stirred at room temperature for 5.5 hours. Further,TEA (0.1 ml) was added and the mixture was stirred at room temperaturefor 2.5 hours. Then, 1M sodium hydroxide (0.786 ml) and methanol (4 ml)were added, and the reaction mixture was stirred at room temperature for30 minutes to cleave the ester. After neutralization, most of thesolvent was evaporated, the resulting precipitate was collected, washedwith ethyl acetate and water, and recrystallized (ethanol) to give Co150 (71 mg).

Example 44

Chlorooxoacetic acid ethyl ester (190 mg) and TEA (1 ml) were added to asolution of Co 97 (285 mg) in chloroform (12 ml), and the mixture wasstirred at room temperature for 16 hours. The reaction mixture wasextracted with chloroform, washed with water, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified with silica gel column chromatography (eluent;chloroform:methanol=50:1), and recrystallized(chloroform/methanol/hexane) to give Co 159 (103 mg).

Example 45

Benzoyl isothiocyanate (1.2 ml) was added to a solution of Co 97 (1.2 g)in chloroform (30 ml) under ice cooling, and the mixture was stirred atroom temperature for 3 hours. The precipitated crystals were collected.To the obtained crystals, 40% methylamine/methanol was added and thereaction mixture was stirred at room temperature for 1 hour,concentrated under reduced pressure, and purified with silica gel columnchromatography to give 1-(4-morpholino-2-phenylquinazoline-6-yl)thiourea(1.1 g). To 266 mg of this compound, ethanol (5 ml), methanol (3 ml) and40% chloroacetaldehyde (300 mg) were added. The reaction mixture wasstirred for 4 days, diluted with ethyl acetate, washed with saturatedaqueous sodium hydrogencarbonate, and dried over anhydrous magnesiumsulfate. The residue was purified with silica gel column chromatography(hexane:ethyl acetate=2:1), and recrystallized (ethanol/hexanc) to giveCo 160 (49 mg).

Example 46

Acetic acid (5 ml) and 48% hydrobromic acid (5 ml) were added to Co 91(500 mg), and the reaction solution was refluxed for 13 hours, and thenconcentrated. The reaction mixture was neutralized with 1M sodiumhydroxide and saturated aqueous sodium hydrogencarbonate, and extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The obtained solid waspurified with silica gel column chromatography (hexane:ethylacetate=1:1), and recrystallized (ethanol) to give Co 162 (112 mg).

Example 47

3-Morpholinopropanol (93 mg) and a free form of Co 50 (203 mg) wereadded to a solution of diethyl azodicarboxylate (0.101 ml) andtriphenylphosphine (168 mg) in THF (20 ml) and the mixture solution wasstirred at 60C for 13 hours. Additional diethyl azodicarboxylate (0.1ml), triphenylphosphine (170 mg) and 3-morpholinopropanol (93 mg) wereadded and the mixture was stirred at 60C. This addition of the reagentswas repeated again. After the reaction mixture was allowed to cool,water and ethyl acetate were added, and the reaction mixture wasbasified with saturated aqueous sodium hydrogencarbonate. Afterextraction with ethyl acetate, the solution was washed with brine. Afterthe solution was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure. The obtained residue was purifiedwith silica gel column chromatography (chloroform:methanol=98:2), andrecrystallized (methanol) to give a free form of Co 58 (174 mg). Theobtained free form (71 mg) was subjected to salt formation as describedin EXAMPLE 18, and recrystallized (methanol) to give hydrochloride of Co58 (68 mg).

Example 48

Potassium carbonate (1.10 g) was added to a solution of Co 61 (1.48 g)in methanol (15 ml) and water (15 ml). After the mixture was stirred at80C, additional methanol (8 ml) and water (8 ml) were added and themixture was stirred at 80C for 12 hours. After the reaction mixture wasallowed to cool, crystals were collected, purified with silica gelcolumn chromatography (chloroform:methanol=98:2), and crystallized(methanol) to give a free form of Co 59 (1.13 g). The obtained free form(160 mg) was subjected to salt formation as described in EXAMPLE 18, andrecrystallized (methanol) to give dihydrochloride of Co 59 (146 mg).

Example 49

Anhydrous trifluoroacetic acid (1.07 ml) and dimethylaminopyridine (78mg) were added to a solution of a free form of Co 31 (2.21 g) inpyridine (70 ml) under ice cooling. After the mixture solution wasstirred for 1 hour, more anhydrous trifluoroacetic acid (0.5 ml) anddimethylaminopyridine (30 mg) were added, and the mixture was stirredunder ice cooling for 1 hour. The solvent was evaporated under reducedpressure, water and ethyl acetate were added, and the precipitatedcrystals were filtered and washed with ethyl acetate to give Co 60 (2.66g).

Example 50

Water (0.645 ml), dibromoethane (1.11 ml), tetrabutylammoniumhydrogensulfate (22 mg) and 2M aqueous sodium hydroxide (2.58 ml) wereadded to a free form of Co 50 (1.29 g), and the mixture was stirred 60Cfor 6 hours. Chloroform was added to the mixture, unsoluble materialswere filtered, and the filtrate was extracted with chloroform and thenwashed with brine. After the solution was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and theobtained residue was purified with silica gel column chromatography(chloroform:methanol=98:2) to give Co 62 (376 mg).

Example 51

1-Methylpiperazine (139 mg) and potassium carbonate (256 mg) were addedto a solution of Co 62 (211 mg) in DMF (5 ml) and the mixture solutionwas stirred at 60C for 4 hours. The solvent was evaporated under reducedpressure, water and THF were added to the obtained residue, the mixturewas extracted with ethyl acetate, and then the solvent was evaporatedunder reduced pressure. The obtained residue was purified with silicagel column chromatography (chloroform:methanol=97:3˜95:5) to give a freeform of Co 64 (198 mg). The obtained free form (198 mg) was subjected tosalt formation as described in EXAMPLE 18, and recrystallized (methanol)to give trihydrochloride of Co 64 (160 mg).

Example 52

tert-Butyl piperazine-1-carboxylate (285 mg) and potassium carbonate(282 mg) were added to a solution of Co 62 (232 mg) in DMF (5 ml) andthe mixture solution was stirred at 60C for 17 hours. The solvent wasevaporated under reduced pressure, water was added to the obtainedresidue, and the resulting mixture was extracted with ethyl acetate andthen washed with brine. After the solution was dried over anhydroussodium sulfate, the solvent was evaporated under reduced pressure andthe obtained residue was purified with silica gel column chromatography(chloroform:methanol=99:1) to give solid (227 mg). 4M Hydrogenchloride/ethyl acetate (1 ml) were added to a solution of the obtainedsolid (212 mg) in dioxane (3 ml) and methanol (3 ml), and the mixturewas stirred at room temperature for 4 hours. The resulting mixture wasconcentrated and the residue was recrystallized (methanol) to give Co 69(144 mg).

Example 53

Paraformaldehyde (15 mg) and acetic acid (81 ml) were added to asolution of a free form of Co 59 (216 mg) in THF (3 ml). After themixture was stirred at room temperature for 10 minutes, sodiumtriacetoxyborohydride (199 mg) was added and the mixture was stirred atroom temperature for 21 hours. Then, liquid formaldehyde (0.44 ml),acetic acid (5.5 ml) and sodium triacetoxyborohydride (704 mg) wereadded in 3 divided portions, and the reaction solution was stirred atroom temperature for 4 days. The reaction mixture was neutralized with2M aqueous sodium hydroxide, and THF was added. After the reactionsolution was extracted with ethyl acetate, it was washed with brine.After it was dried over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure, and the obtained residue was purifiedwith silica gel column chromatography (chloroform methanol=98:2) to givea free form of Co 70 (162 mg). The obtained free form (48 mg) wassubjected to salt formation as described in EXAMPLE 18, andrecrystallized (methanol) to give dihydrochloride of Co 70 (53 mg).

Example 54

After a free form of Co 50 (322 mg), 1,3-dioxolane-2-one (814 mg) andpotassium carbonate (192 mg) were stirred at 100C for 2 hours, more1,3-dioxolane-2-one (680 mg) was added and the mixture was stirred at100C for 17 hours. Then, DMF (3 ml) was added and the mixture wasstirred at 100C for 2 hours, and further 1,3-dioxolane-2-one (670 mg)was added and the mixture was stirred at 100C for 20 hours. After thereaction mixture was allowed to cool, the solvent was evaporated underreduced pressure, and water was added. Then, 1M aqueous hydrochloricacid was added until bubbles no longer appeared. The precipitatedcrystals were collected and recrystallized (methanol) to give Co 77 (164mg).

Example 55

Phosphorus oxychloride (10 ml) was added to Rco 48 (1.07 g), and themixture was refluxed for 2.5 hours. The solvent was evaporated, and thereaction mixture was azeotropically concentrated with toluene. THF (15ml) was added to the obtained residue. After morpholine (10 ml) wasslowly added in dropwise under ice cooling, the ice bath was removed andthe reaction mixture was refluxed for 30 minutes. Ethyl acetate and THFwere added to the reaction mixture and the mixture was washed with waterand brine. After it was dried over anhydrous sodium sulfate, the solventwas evaporated under reduced pressure and the obtained residue waspurified with silica gel column chromatography(chloroform:methanol=98:2) to give bis(morpholinoamido)2-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidine-2-yl)phenylphosphonate(594 mg). Formic acid (4 ml) was added to this compound (360 mg) and themixture was stirred at 100C for 3 days. The solvent was evaporated underreduced pressure, ethyl acetate and water were added, and the mixturewas neutralized with saturated aqueous sodium hydrogencarbonate underice cooling. The precipitated crystals were filtered to give crystals(162 mg). The obtained crystals (123 mg) were recrystallized(methanol-THF) to give Co 79 (122 mg).

Example 56

Dioxane (3.9 ml) and 6M hydrochloric acid (5.5 ml) were added to Co 80(220 mg), and the mixture was refluxed for 3 days. After the reactionmixture was allowed to cool, it was neutralized, extracted with amixture solution of ethyl acetate and THF, and washed with brine. Afterit was dried over anhydrous sodium sulfate, the solvent was evaporatedunder reduced pressure, and the obtained residue was purified withsilica gel column chromatography (chloroform:methanol=96:4) to givecrystals (83 mg). The obtained crystals (81 mg) were recrystallized(THF-methanol) to give Co 81 (53 mg).

Example 57

After a solution of a free form of Co 168 (151 mg) in pyridine (9 ml)was cooled in an ice bath, acetic anhydride (4.5 ml) was added, and themixture was stirred under ice cooling. After the reaction completed, thereaction mixture was poured into water with ice, extracted with ethylacetate, and washed with brine. After it was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure to give afree form of Co 183 (158 mg). The obtained free form (156 mg) wassubjected to salt formation as described in EXAMPLE 18, and the obtainedcrystals were recrystallized (methanol) to give hydrochloride of Co 169(93 mg).

Example 58

2-Morpholinoethanol (806 mg) was added in dropwise to a solution of 60%sodium hydroxide (63 mg) in DMF (5 ml), and the mixture solution wasstirred at room temperature for 15 minutes. Then, a free form of Co 179(285 mg) was added and the mixture was stirred at 60C for 23 hours.Then, a mixture, which was prepared by adding 2-morpholinoethanol (806mg) in dropwise to 60% sodium hydroxide (63 mg) in DMF (1 ml) andstirring at room temperature for 15 minutes, was added in dropwise tothe reaction mixture and the resulting mixture was stirred at 60C. Thisaddition of sodium 2-morpholinoethoxide was conducted 3 times. Thesolvent was evaporated under reduced pressure, water and THF were addedto the obtained residue, and the mixture was extracted with ethylacetate and then washed with brine. After it was dried over anhydroussodium sulfate, the solvent was evaporated under reduced pressure, andthe obtained residue was purified with silica gel column chromatography(chloroform:methanol=95:5) to give a free form of Co 192 (529 mg). Theobtained free form (404 mg) was subjected to salt formation as describedin EXAMPLE 18, and the obtained crystals were recrystallized (methanol)to give dihydrochloride of Co 192 (320 mg).

What is claimed is:
 1. A fused heteroaryl compound of formula (Ib):

or a salt thereof, wherein: B is a pyridine ring; R² and R³ are combinedtogether with the N atom adjacent thereto to form —NR²R³ which is anitrogen-containing saturated heterocyclic group which may have one ortwo substituents selected from the group consisting of —OH, ═O and -alower alkyl; R^(4b) is —an aryl which has one to five substituentsselected from Group A⁴; wherein Group A⁴ is selected from the groupconsisting of -a lower alkylene-OR, —CONRR′, —NR—CO-Cyc¹, —NR—SO₂-Cyc¹,—OR, —NRR′, —O-a lower alkylene-NRR′ and —O-a lower alkylene-(anitrogen-containing saturated ring which may have one to fivesubstituents selected from Group A), wherein Cyc¹, is —an aryl which mayhave one to five substituents selected from Group A, -a heteroaryl whichmay have one to five substituents selected from Group A, or -anitrogen-containing saturated heterocyclic group which may have one tofive substituents selected from Group A; wherein Group A is selectedfrom the group consisting of -a lower alkyl, -a lower alkenyl, -a loweralkynyl, -a halogen, -a halogenated lower alkyl,-a lower alkylene —OR,—NO₂, —CN, ═O, —OR, —O-a halogenated lower alkyl, —O-a loweralkylene-NRR′, —O-a lower alkylene-OR, —O-a lower alkylene-an aryl, —SR,—SO₂ lower alkyl, —SO-a lower alkyl, —COOR, —COO-a lower alkylene-anaryl; —COR, —CO-an aryl, -an aryl, —CONRR′, —SO₂NRR′, —NRR′, —NR″-alower alkylene-NRR′, —NR′-a lower alkylene-OR, —NR-a lower alkylene-anaryl, —NRCO-a lower alkyl, —NRSO₂-a lower alkyl, -a cycloalkyl and -acycloalkenyl; and wherein R, R′ and R″, may be the same or different andare independently selected from the group consisting of H or a loweralkyl.
 2. The fused heteroaryl compound or a salt thereof according toclaim 1, wherein R² and R³ form —NR²R³ which is -morpholino.
 3. Thefused heteroaryl compound or a salt thereof according to claim 1,wherein R^(4b) is a phenyl which has at least one substituent which isselected from —OH, —CH₂OH and —CONH₂.
 4. The fused heteroaryl compoundor a salt thereof according to claim 1, wherein the fused heteroarylcompound is selected from the group consisting of3-(4-morpholinopyrido[4,3-d]pyrimidin-2-y])phenol,3-(4-morpholinopyrido[3,2-d]pyrimidin-2-yl)phenol, and3-(4-morpholinopyrido[3,4-d]pyrimidin-2-y])phenol.
 5. A pharmaceuticalcomposition consisting a fused heteroaryl compound or a salt thereofaccording to claim 1 and a pharmaceutically acceptable carrier.
 6. Amethod of treating a disorder in a patient, said disorder havingabnormal cell growth associated with phosphatidylinositol 3 kinasecomprising administering to the patient a therapeutically effectiveamount of the fused heteroaryl compound or a salt thereof according toclaim
 1. 7. A method of claim 6, wherein disorder has abnormal cellgrowth associated with phosphatidylinositol 3 kinase p110α subtype. 8.The method of claim 6, wherein the disorder is cancer.
 9. A method ofclaim 8, wherein cancer is selected from the group consisting ofleukemia, skin cancer, bladder cancer, breast cancer, uterus cancer,lung cancer, colon cancer, prostate cancer, ovary cancer, pancreascancer, renal cancer, gastric cancer and brain tumor.